Chirality transfers through sequential sigmatropic rearrangements of allylic vicinal diols: Development and application to total synthesis of (-)-kainic acid

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DOI: 10.1002/ejoc.201200523

Chirality Transfers through Sequential Sigmatropic Rearrangements of Allylic

Vicinal Diols: Development and Application to Total Synthesis of (–)-Kainic

Acid

Katsunori Kitamoto,^[a]Yasuaki Nakayama,^[a]Mana Sampei,^[a]Masato Ichiki,^[a]

Naoya Furuya,^[a]Takaaki Sato,*^[a]and Noritaka Chida*^[a]

Keywords: Rearrangement / Sigmatropic rearrangement / Total synthesis / Chirality transfer / Allylic compounds /

Diastereoselectivity

A detailed description is presented of two sequential sigma-

tropic rearrangements starting from enantiopure allylic vici-

nal diols. Starting from the same allylic diol, the sequential

Claisen/Claisen rearrangement can install two identical

functional groups in a one-pot reaction, whereas, the sequen-

tial Claisen/Overman rearrangement can introduce two dif-

ferent functional groups, both occurring without protecting

group manipulation. Both sequential reactions proceeded

with complete stereoselectivity, which was easily predictable

by the judicious choice of two factors regarding the allylic

diols: (1) the stereochemistry of the hydroxy groups and

(2) the geometry of the olefin. To demonstrate this sequential

rearrangement methodology, we accomplished the total syn-

thesis of (–)-kainic acid, whose three contiguous stereocen-

ters were completely established by three chirality transfer

reactions (S_N2Ј and sequential Claisen/Overman reactions)

of flexible acyclic intermediates derived from D-arabinose.

tive protection of the homoallylic hydroxyl group (1Ǟ4),

which is not trivial because the allylic alcohol is generally

more reactive than the homoallylic alcohol. After the chi-

rality transfer reaction of 4, the extra deprotection step

5Ǟ2 is also required. In this paper, we report the full de-

tails of stereocontrolled chirality transfer reactions using se-

quential sigmatropic rearrangements of acyclic allylic diols

without protecting group manipulation (1Ǟ2Ǟ3). This

methodology was then applied to the total synthesis of (–)-

kainic acid.

Introduction

Chirality transfer reactions of enantiopure allylic

alcohols are promising synthetic tools for the preparation

of chiral compounds.^[1]The newly generated stereochemis-

try is independent of the conformational environment in the

starting material and depends on two factors with respect

to the allylic alcohol: (1) the stereochemistry of the hy-

droxyl group and (2) the geometry of the olefin. This high

stereocontrol can be observed even in flexible acyclic com-

pounds. To render the chirality transfer more useful, our

laboratory group was interested in its application to allylic

vicinal diol 1, which is readily available through a Sharpless

asymmetric dihydroxylation^[2]and transformations from

natural occurring polyols, such as monosaccharides and

tartaric acid (Scheme 1). Allylic diol 1 would potentially en-

able two chirality transfer reactions (1Ǟ2Ǟ3).^[3]The first

chirality transfer reaction of 1 would result in the stereo-

selective installation of functional group A, accompanied

by transposition of the double bond to provide allylic

alcohol 2. Subsequently, allylic alcohol 2 could undergo a

second chirality transfer reaction to introduce functional

group B. However, most chirality transfers require the selec-

Scheme 1. Allylic diol 1 providing opportunities for sequential chi-

rality transfers.

[a] Department of Applied Chemistry, Faculty of Science and

Technology, Keio University,

Results and Discussion

3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan

Fax: +81-45-566-1551

As a practical demonstration of sequential chirality

transfers for allylic diol 1, we envisioned two types of new

sigmatropic rearrangements involving the Claisen re-

arrangement (Scheme 2a).^[4–6]We selected the Claisen re-

E-mail: takaakis@applc.keio.ac.jp

chida@applc.keio.ac.jp

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200523.

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T. Sato, N. Chida et al.

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arrangement because both Eschenmoser- and Johnson-type entirely depend on the stereochemistry of the two second-

reactions can proceed from a free allylic alcohol as the ary alcohols and the geometry of the olefin. An example of

starting material. These reaction conditions could also be the stereochemical relationship between the allylic diols and

compatible with free allylic diols and could potentially elim- the rearranged products is shown in part b of Scheme 2.

inate the protecting group manipulations during the two The sequential Claisen/Claisen rearrangement of (E)-syn-1

sigmatropic rearrangements. In the sequential Claisen/ would give syn-7, however, the reaction of (Z)-syn-1 would

Claisen rearrangement (1Ǟ6Ǟ7), the treatment of allylic result in the formation of anti-7. On the other hand, the

diol 1 under thermal Claisen conditions would initiate the rearrangement of the anti-diols would result in the synthe-

first rearrangement to afford 6, which could then instantly ses of the opposite diastereomers. Namely, the reaction of

undergo the second Claisen rearrangement. The Claisen/ (E)-anti-1 would give anti-7, and the reaction of (Z)-anti-1

Claisen rearrangement of 1 would install two identical func- would result in the formation of syn-7. Considering that

tional groups in a one-pot reaction, however, the Claisen/ both enantiomers of diols are easily available, it is note-

Overman rearrangement could introduce two different worthy that all four possible diastereomers of 7 could be

functional groups starting from the same allylic diol synthesized by choosing the appropriate combination of the

(1Ǟ8Ǟ9). In this case, the key to success would be in the diol stereochemistry and the olefin geometry.

control of the single or double Claisen rearrangement from

The geometry of the olefin, as one of the stereochemical

the same allylic diol. The Claisen/Overman rearrangement determining factors, was easily controlled by choosing the

is inherently more challenging, because it requires the sup- appropriate Wittig-type reaction conditions (Scheme 3).

pression of the second competitive Claisen rearrangement The synthesis of syn-allylic diols 14a–14c commenced with

(8Ǟ6Ǟ7) following the first rearrangement.^[7]If the single a Swern oxidation^[11]of 11,^[12]which was prepared from the

rearrangement of 1 is completely controlled, however, the inexpensive l-tartaric acid dimethyl ester (10) in three steps.

resulting allylic alcohol 8 could undergo a variety of chiral- The resulting unstable aldehyde 12 was quickly exposed to

ity transfer reactions including the Overman rearrangement three different Wittig-type conditions. (E)-olefin 13a^[13]was

(8Ǟ9).^[8–10]

obtained, when the classic stable ylide was used, whereas

Ando’s conditions^[14]led to (Z)-olefin 13b as the major

product. High selectivity was also observed in the synthesis

of trisubstituted olefin 13c. Enoates 13a–13c were then

Scheme 2. (a) Two types of sequential sigmatropic rearrangements

based on the Claisen rearrangement. (b) The stereochemical rela-

tionship between the allylic diol 1 and product 7 in the sequential

Claisen/Claisen rearrangement.

One of the practical advantages of these sequential re-

arrangements would be the predictable stereochemical out-

come, because of the tight six-membered chair-like transi-

tion state. In flexible acyclic compounds, the newly gener-

ated stereochemistry would be independent of the confor-

Scheme 3. Reagents and conditions: (a) (COCl)₂, DMSO (dimethyl

sulfoxide), Et₃N, CH₂Cl₂, –78 °C; (b) Ph₃P=CHCO₂Et, toluene,

100 °C; (c) (PhO)₂P(O)CH₂CO₂Et, NaH, THF (tetrahydrofuran),

–78 °C; (d) MeO₂CCHMePPh₃⁺Br^–, Et₃N, CH₂Cl₂, 0 °C; (e) DI-

BAL, toluene, –78 °C; (f) BnBr, NaH, DMF (N,N-dimethylform-

mational environment of the starting material and would amide), 0 °C to room temp.; (g) 80% AcOH, room temp.

2

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Chirality Transfers through Sequential Sigmatropic Rearrangements

transformed into allylic diols 14a–14c, respectively, using Table 1. Optimization of reaction conditions in the sequential

Claisen/Claisen rearrangement.^[a]

the same straightforward sequence involving reduction by

DIBAL (diisobutylaluminum hydride), protection by a

benzyl (Bn) group, and cleavage of the acetonide. The anti-

allylic diols 14d–14f were synthesized from lactol 16,^[15,16]

which was derived from d-ribose (15, Scheme 4). The Wittig

reaction of lactol 16 resulted in relatively lower selectivity

to give 17d^[17]and 17e,^[18]however, trisubstituted olefin 17f

was synthesized in high stereoselectivity. Enoates 17d–17f

were then converted into allylic diols 14d–14f using a four-

step sequence [MPM (p-methoxybenzyl) protection,

DIBAL reduction, Bn protection, cleavage of the aceto-

nide].

Entry Reagent

Acid

T [°C]

Yield [%]^[b]

1

MeC(OEt)₃

EtCO₂H

140

180

18a, 14

18a, 22

19a, 87

2

MeC(OEt)₃

p-NO₂C₆H₄CO₂H

o-NO₂C₆H₄OH

none

3

MeC(OEt)₃

MeC(OMe)₂NMe₂

4^[c]

[a] 14a (50 μmol), MeC(OEt)₃(0.03 m solution) or MeC(OMe)₂-

NMe₂(20 equiv.), acid (0.1 equiv.) in a sealed tube, 2 d. [b] Yield

of isolated product after purification by column chromatography

on silica gel. [c] tBuPh (0.03 m solution) was used as solvent.

Table 2. Substrate scope in the sequential Claisen/Claisen re-

arrangement.^[a]

Scheme 4. Reagents and conditions: (a) EtO₂CCH=PPh₃,

PhCO₂H, benzene, 80 °C; (b) EtO₂CCH=PPh₃, CH₂Cl₂, room

temp.;

(c) MeO₂CCMe=PPh₃,

CH₂Cl₂,

room

temp.;

(d) MPMOC(=NH)CCl₃, CSA (camphorsulfonic acid), CH₂Cl₂,

room temp.; (e) DIBAL, toluene, –78 °C; (f) BnBr, NaH, DMF,

0 °C to room temp.; (g) 80% AcOH, room temp.

First, we investigated our sequential Claisen/Claisen re-

arrangement by using Johnson’s conditions with (E)-allylic

syn-diol 14a (Table 1). A solution of 14a and MeC(OEt)₃

in the presence of a catalytic amount of EtCO₂H was

heated at 140 °C in a sealed tube for 2 days to give bis(ester)

18a in 14% yield (Table 1, Entry 1). The nature of the acid

had little effect on the isolated yield of 18a (Table 1, En-

tries 2 and 3).^[19]However, there was a significant improve-

ment in the yield using Eschenmoser’s conditions, em-

ploying an excess amount of MeC(OMe)₂NMe₂at 180 °C,

to give bis(amide) 19a in 87% yield, without the isolation

of the singly rearranged product (Table 1, Entry 4). As ex-

pected, the reaction proceeded in a stereoselective manner,

giving syn-bis(amide) 19a as a single diastereomer.

The investigation of the scope of the sequential Claisen/

Claisen rearrangement with a variety of allylic diols re-

vealed the remarkable stereoselectivity (Table 2). The reac-

[a] 14 (50 μmol), MeC(OMe)₂NMe₂(20 equiv.), tBuPh (0.03 m

solution), 180 °C in a sealed tube, 2 d. [b] Yield of isolated product

after purification by column chromatography on silica gel. [c] The

tions of both (E)-allylic syn-diol 14a and (Z)-allylic syn-diol reaction was complete in 1 d.

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14b took place in a completely diastereoselective manner, bility of cyclic orthoester 22a. Because the corresponding

providing 19a and 19b in 87% and 81% yields, respectively cyclic orthoamide 23a would be less stable than cyclic or-

(Table 2, Entries 1 and 2). The geometry of the olefin had thoester 22a, the Eschenmoser-type Claisen was then at-

little effect on the yields or the rates of the rearrangements. tempted, prompting the generation of acyclic N,O-ketene

The rearrangement of trisubstituted olefin 14c gave us ac- acetal 25a (Table 3, Entry 2). Gratifyingly, treatment of 14a

cess in enantiopure form to two contiguous stereocenters, in o-xylene with 2.0 equiv. of MeC(OMe)₂NMe₂at room

including a highly congested quaternary carbon, which was temperature for 3 h led to the formation of orthoamide 23a,

otherwise difficult to synthesize (Table 2, Entry 3). The rate which was heated in the same vessel at 160 °C for 4 d to

of the reaction with anti-diols 14d and 14e proved to be afford 27a in 52% yield. Under these conditions, the doubly

faster than that with the syn-diols, with 19b and 19a iso- rearranged byproduct 19a was concomitantly generated in

lated in 88% and 80% yields, respectively (Table 2, Entries 4 9% yield, because of the presence of an excess amount of

and 5). The synthesis of the identical bis(amides) was real- MeC(OMe)₂NMe₂. However, the use of 1.0 equiv. of the

ized starting from both syn- and anti-diols, showing the reagent resulted in a significant decrease in yield, along with

flexibility in designing synthetic routes toward useful chiral the recovery of a large amount of the starting material 14a

compounds. The reaction of trisubstituted olefin 14f de- (Table 2, Entry 3). We finally found that the addition of

rived from an anti-diol proceeded in good yield as well 500 wt.-% MS (molecular sieves, 4 Å), after the formation

(Table 2, Entry 6).

of orthoamide 23a, dramatically improved the yield to give

The stereochemical determination of acyclic bis- the singly rearranged product 27a in 91% yield (Table 2,

(amides) 19 derived from the sequential Claisen/Claisen re- Entry 4). Although the role of the MS was not clear, they

arrangement was not trivial, because these compounds can may selectively decompose the excess amount of MeC-

adopt flexible conformations. To circumvent this problem, (OMe)₂NMe₂through adsorption of the liberated meth-

we envisioned a unique transformation of the bis(amides) anol. In fact, when the MS were added at the beginning of

into cyclic compounds by using the Schwartz reagent. An the reaction, the formation of orthoamide 23a was sup-

example of this conversion using bis(amide) 19c is shown pressed.

in Scheme 5.^[20]Partial reduction of bis(amide) 19c, bearing

an internal olefin, with the Schwartz reagent gave bis(al- Table 3. Optimization of reaction conditions in the orthoamide-

type Claisen rearrangement.^[a]

dehyde) 20c, which then underwent an intramolecular aldol

condensation with piperidine. The stereochemistry of the

resulting cyclopentenal 21c was convincingly established by

a NOESY experiment, which showed that the sequential

Claisen/Claisen rearrangement proceeded through the ex-

pected six-membered transition state.

Entry Reagent

Equiv. Additive

Yield [%]^[b]

1^[c]

MeC(OEt)₃

MeC(OMe)

₂NMe₂

MeC(OMe)

₂NMe₂

MeC(OMe)

₂NMe₂

2.0

o-nitrophenol

26a, 0

18a, 0

2

none

27a, 52 19a, 9

27a, 16 19a, 0

Scheme 5. An example of stereochemical determination in the se-

quential Claisen/Claisen rearrangement.

3

1.0

2.0

4^[d]

mol. sieves, 4 Å 27a, 91 19a, 0

Having successfully developed the sequential Claisen/

Claisen rearrangement, we turned our attention to the more

challenging Claisen/Overman version. As mentioned in

Scheme 2, the suppression of the concomitant double re-

arrangement (8Ǟ6Ǟ7) is a critical issue. Therefore, we

[a] 14a (140 μmol), MeC(OEt)₃or MeC(OMe)₂NMe₂, o-xylene

(0.03 m solution), room temp., 3 h, then 160 °C in a sealed tube,

4 d. [b] Yield of isolated product after purification by column

chromatography on silica gel. [c] o-Nitrophenol (0.1 equiv.) was

added. [d] MS (4 Å, 500 wt.-%) was added after the formation of

planned to take advantage of the use of cyclic orthoester orthoamide 23a.

22a (Table 3, Entry 1). Treatment of (E)-allylic syn-diol 14a

with 2.0 equiv. of MeC(OEt)₃in o-xylene at room tempera-

The developed procedure through the cyclic orthoamide

ture promoted the formation of cyclic orthoester 22a. How- proved to be a reliable means to obtain the singly re-

ever, even in the presence of a catalytic amount of o-ni- arranged product from a variety of allylic diols 14 (Table 4).

trophenol, cyclic orthoester 22a did not afford the singly The resulting allylic alcohol 27 was subsequently trans-

rearranged product 26a, probably because of the high sta- formed into trichloroimidates 28, which then underwent an

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Chirality Transfers through Sequential Sigmatropic Rearrangements

Overman rearrangement at 140 °C in the presence of diols 14d–14f also proceeded in high yields (Table 4, En-

[21]

K₂CO₃

to give trichloroacetamides 29. The sequential tries 4–6). Interestingly, the formation of the orthoamides

Claisen/Overman rearrangement of (E)-allylic syn-diol 14a from anti-diols 14d–14f required an elevated temperature

and (Z)-allylic syn-diol 14b proceeded with similar high and prolonged reaction time compared to the correspond-

yields (Table 4, Entries 1 and 2). The yields of both the first ing syn-diols (60 °C, 6 h vs. room temp., 3 h), whereas the

Claisen rearrangement and the following Overman re- Claisen rearrangement of the anti-diols proceeded much

arrangement were independent of the olefin geometry. The faster than syn-diols 14a and 14b (160 °C, 1.5 d vs. 160 °C,

reaction of trisubstituted olefin 14c proceeded as well, al- 4 d). All of the allylic diols showed complete diastereoselec-

though the second Overman rearrangement resulted in tivity in both sigmatropic rearrangements. Although the

slightly lower yields because of the large steric hindrance in Claisen/Overman sequence was in fact two separate re-

the molecule (Table 4, Entry 3). The rearrangements of anti- arrangements programmed sequentially, it precluded pro-

tecting group manipulation and succeeded to provide highly

functionalized chiral building blocks.

The stereochemical determination of the sequential

Claisen/Overman rearrangement products was achieved

Table 4. Substrate scope in the sequential Claisen/Overman re-

arrangement.^[a]

through their conversion to cyclic compounds (Scheme 6).

For example, the hydrolysis of 29c with KOH in tBuOH/

H₂O at 70 °C gave γ-lactam 30c in 56% yield. The stereo-

chemistry of 30c was unambiguously confirmed by a

NOESY experiment.

Scheme 6. An example of stereochemical determination in the se-

quential Claisen/Overman rearrangement.

The proposed mechanistic details of the two sequential

sigmatropic rearrangements are shown in Scheme 7. Al-

though the trisubstituted olefin needed a slightly longer re-

action time, the rate of the reaction was largely independent

of the olefin geometry. On the other hand, the stereochem-

istry of the diols had a considerable effect on the rates of

individual steps in the Claisen/Overman process. The for-

mation of orthoamide 32a from the syn-diol 31 was much

faster than the formation of orthoamide 32b from the anti-

diol 31 (room temp., 3 h vs. 60 °C, 6 h), whereas the subse-

quent Claisen rearrangement of the orthoamide 32a was

slower than that of orthoamide 32b (160 °C, 4 d vs. 160 °C,

1.5 d). In the subsequent Overman rearrangement, no sig-

nificant difference was observed between the syn- and anti-

diols (140 °C, 2 h). These results clearly indicated that the

rates of the reactions depend on the stereochemical configu-

ration of the cyclic orthoamides 32. In other words, the ste-

[a] (i) For syn-diols 14a–c (50 μmol): MeC(OMe)₂NMe₂

ric repulsion between the cis substituents in the orthoamide

(2.0 equiv.), o-xylene (0.03 m solution), room temp., 3 h, then

32b could suppress its formation and promote its cleavage

160 °C in a sealed tube, 4 d. For anti-diols 14d–f (50 μmol): MeC-

prior to the Claisen rearrangement. In addition, the re-

quired higher reaction temperature and more prolonged re-

action time in the orthoamide-type Claisen rearrangement

versus the conventional Eschenmoser-type rearrangement

would change the rate-determining step from the rearrange-

ment step to the cleavage of the cyclic orthoamides to form

(OMe)₂NMe₂(2.0 equiv.), o-xylene (0.03 m solution), 60 °C, 6 h,

then 160 °C in a sealed tube, 1.5 d. (ii) CCl₃CN (2.0 equiv.), DBU

(1,8-diazabicyclo[5.4.0]undec-7-ene, 1.0 equiv.), CH₂Cl₂(0.05 m

solution), 0 °C to room temp., 3 h; (iii) K₂CO₃(25 mol-%), o-xylene

(0.1 m solution), 140 °C in a sealed tube, 2 h. [b] Yield of isolated

product after purification by column chromatography on silica gel.

[c] The reaction was performed at 180 °C for 1 d.

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N,O-ketene acetal 33. The rate of the second Overman re-

arrangement was independent of the stereochemistry, which

was likely because of the flexible configuration. Considering

the fact that the rate of the sequential Claisen/Claisen re-

arrangements showed a similar tendency to the first Claisen

rearrangement in the Claisen/Overman process (180 °C, 2 d

for syn-diols vs. 180 °C, 1 d for anti-diols), the Claisen/

Claisen process might also take place through cyclic or-

thoamide 32. Monitoring the sequential Claisen/Claisen re-

action by TLC also suggested the presence 32.

Scheme 8. Synthetic plan toward (–)-kainic acid (41).

The synthesis of (–)-kainic acid (41) began by selective

MOM (methoxymethyl) protection of primary alcohol 42,

which was readily available from d-arabinose (36) by a

known two-step reaction sequence (Scheme 9).^[27]The re-

maining secondary alcohol was transformed into the mesyl-

ate. The stage was now set for the crucial S_N2Ј reaction of

Scheme 7. Mechanistic details of the sequential sigmatropic re-

arrangements.

With practical sequential sigmatropic rearrangements in

hand to access useful chiral compounds, we then applied

the methodology to the total syntheses of biologically active

natural products. (–)-Kainic acid (41),^[22]isolated from the

Japanese marine alga Digenea simplex,^[23,24]was chosen to

showcase this methodology. (–)-Kainic acid (41) was origi-

nally used in anthelmintic and insecticide preparations^[25]

and was recently applied to neuropharmacology, because of

its ability to cause responses that mimic neuronal disorders,

such as Alzheimer’s disease.^[26]Our synthetic plan toward

the total synthesis of (–)-kainic acid is outlined in Scheme 8.

The salient feature of our strategy was the installation of

the three contiguous stereocenters (C-2, C-3, and C-4) by

taking advantage of three chirality transfers derived from

the secondary hydroxy groups embedded in d-arabinose

(36). The first chirality transfer was the S_N2Ј reaction of

allylic mesylate 37 to introduce the propenyl unit at the C-

4 position. The sequential Claisen/Overman rearrangement

of (E)-allylic anti-diol 39 was then employed to establish

the other two stereocenters (C-2 and C-3). After the three

stereocenters were established in flexible acyclic intermedi-

ates through chirality transfer reactions, the cyclization of

40 would lead to (–)-kainic acid (41).

Scheme 9. Total synthesis of (–)-kainic acid (41). CAN = ce-

rium(IV) ammonium nitrate, DEAD = diethyl azodicarboxylate,

Ms = methanesulfonyl, NMO = N-methylmorpholine oxide, TMS

= trimethylsilyl.

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Chirality Transfers through Sequential Sigmatropic Rearrangements

γ-mesyloxy α,β-enoate 43 (Table 5). Gratifyingly, the use of

The remaining issue in the total synthesis of (–)-kainic

Ibuka/Yamamoto conditions^[28]with the organocyano- acid (41) was the chemoselective oxidative cleavage of trans-

cuprate in the presence of BF₃·Et₂O initiated the S_N2Ј reac- olefin 47 in the presence of the exo-olefin (Scheme 9). Un-

tion in a stereo- and regioselective manner, giving the de- fortunately, the less hindered exo-olefin was more reactive

sired product 44 in 45% yield (Table 5, Entry 1). The major under Upjohn conditions (OsO₄, NMO, acetone/H₂O). To

byproducts 50 and 51 were generated by S_N2Ј reduction and overcome this issue, we utilized a hydroxy-directed dihy-

subsequent elimination, respectively. The addition of zinc droxylation. First, the MOM group of 47 was removed un-

chloride and lithium chloride, instead of BF₃·Et₂O, slightly der acidic conditions. The resulting allylic alcohol was

improved the yield and suppressed the formation of the by- treated with a catalytic amount of OsO₄with NMO under

products (Table 5, Entry 2). Finally, we found that the anhydrous conditions in CH₂Cl₂, leading to chemoselective

counteranion of the metal salts had a significant effect on dihydroxylation of the allylic alcohol.^[29]The subsequent ex-

the yield. The best result was realized with ZnBr₂and LiBr, posure of the triol to Pb(OAc)₄in a one-pot reaction af-

providing 44 in 86% yield along with a slight amount of 51 forded aldehyde 48. A Kraus–Pinnick oxidation and meth-

(Table 5, Entry 3).

ylation of the resulting carboxylic acid with TMSCHN₂

gave methyl ester 49 in 38% yield (3 steps). The construc-

tion of the pyrrolidine structure was achieved by removal

of the MPM group with CAN followed by a Mitsunobu

reaction of the trichloroacetamide.^[30]Finally, the global de-

protection with KOH in tBuOH/H₂O at 120 °C ac-

complished the total synthesis of (–)-kainic acid (41). The

synthetic sample was found to be identical in all respects

(¹H and ¹³C NMR, IR, HRMS, m.p., and optical rotation)

to the natural product.

Table 5. Optimization of the chirality transfer through S_N2Ј reac-

tion of allylic mesylate 43.^[a]

Conclusions

We described the development of two new sequential sig-

matropic rearrangements of optically pure allylic diols.

Starting from the same allylic diol, we have selectively intro-

duced two identical functional groups (Claisen/Claisen) or

two different functional groups (Claisen/Overman). This

was accomplished without protecting group manipulation,

but by simply changing the amount of MeC(OMe)₂NMe₂

and the addition of MS (4 Å). The sequential Claisen/Over-

man rearrangement was especially useful, because a variety

Entry

Additive

Yield [%]^[b]

44

50

51

1

BF₃·Et₂O

ZnCl₂, LiCl

ZnBr₂, LiBr

45

51

86

18

10

0

37

9

10

2

3^[c]

[a] 43 (120 mmol), tBuLi (8.0 equiv.), 2-bromopropene (4.0 equiv.),

CuCN (2.0 equiv.), BF₃·Et₂O or ZnX₂(2.0 equiv.), LiX₂

(4.0 equiv.), –78 °C, 30 min. [b] Yield of isolated product after puri-

fication by column chromatography on silica gel. [c] 1.31 mmol of of sigmatropic rearrangements are applicable in lieu of the

43 was used.

Overman rearrangement to give highly functionalized chiral

building blocks. A conspicuous feature in these sequential

With the promising first chirality transfer reaction in

reactions was the complete diastereoselection, which was

hand, we turned our attention to the sequential Claisen/

easily predictable by judicious choice of the stereochemistry

Overman rearrangement (Scheme 9). First, (E)-allylic anti-

diol 45 was synthesized. Ethyl ester 44 was reduced with

of the diol and the geometry of the olefin. Mechanistically,

both sequential rearrangements proceeded through a cyclic

LiAlH₄. The protection of the resulting alcohol as the

orthoamide in the Claisen process, whose opening-step was

MPM ether, followed by removal of the acetonide gave all-

ylic diol 45 in 87% yield (3 steps). The key Claisen re-

arrangement of 45 through the cyclic orthoamide required

found to be the rate-determining step. As a demonstration

of the sequential rearrangement, we accomplished the total

synthesis of (–)-kainic acid. The key steps of this synthesis

a slight modification, because of the competing Cope re-

were three chirality transfer reactions (S_N2Ј and sequential

arrangement at 180 °C of the generated allylic diol 46. The

Claisen/Overman reactions) of flexible acyclic intermediates

side reaction was prevented by lowering the reaction tem-

perature, although a prolonged reaction time was necessary

derived from d-arabinose.

(135 °C, 8.5 d). Nevertheless, the reaction afforded only the

singly rearranged product 46 in a diastereoselective fashion

Experimental Section

in 70% yield. The resulting allylic alcohol was converted

into the imidate, which was then heated in a sealed tube at

120 °C in the presence of K₂CO₃to give trichloroace-

toamide 47 in 72% yield. Thus, we successfully established

all of the stereocenters present in (–)-kainic acid (41)

through three chirality transfers.

General Methods: Reactions were performed under an argon atmo-

sphere in oven-dried glassware fitted with rubber septa. Methanol

was distilled from CaSO₄. Benzene, DMF, toluene, tert-butylbenz-

ene, and o-xylene were distilled from CaH₂. All of the distilled sol-

vents, MeCN, CH₂Cl₂, and 1,2-dichloroethane were dried with ac-

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T. Sato, N. Chida et al.

FULL PAPER

tivated molecular sieves (3 Å). THF (dehydrated, stabilizer free)

was from KANTO CHEMICAL CO., INC. Commercial reagents

were used without further purification. Thin layer chromatography

was performed on Merck 60 F254 precoated silica gel plates, which

were visualized by exposure to UV (254 nm) light or stained by

submersion in an ethanolic ninhydrin or ethanolic phosphomolyb-

dic acid solution followed by heating on a hot plate. Flash column

chromatography was performed on silica gel (silica gel 60 N, 63-

210 mesh, KANTO CHEMICAL CO., INC.). The NMR spectro-

(CH), 128.4 (CH), 127.8 (CH), 127.6 (CH), 113.9 (CH), 73.1 (CH₂),

71.5 (CH₂), 71.2 (CH₂), 70.4 (CH₂), 55.4 (CH₃), 40.6 (CH), 39.0

(CH), 37.6 (CH₃), 37.5 (CH₃), 36.5 (CH₂), 35.63 (CH₃), 35.55

(CH₃), 32.8 (CH₂) ppm. HRMS (FAB): calcd. for C₂₉H₄₁N₂O₅[M

+ H]⁺497.3015; found 497.3006.

Bis(dimethylamide) 19c: Following general procedure A, (E)-tri-

substituted allylic syn-diol 14c (20.0 mg, 53.7 μmol) afforded bis(di-

methylamide) 19c (18.1 mg, 66%) as a yellow oil. [α]²_D⁷= +1.6 (c =

0.85, CHCl ). IR (film): ν = 3469, 3028, 2930, 2855, 1639, 1513,

˜

3

1

scopic data were recorded with JEOL ECA-500 spectrometers. H

1396, 1248, 1100 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.25

(m, 5 H), 7.23 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.66

(dd, J = 15.5, 9.5 Hz, 1 H), 5.58 (dt, J = 15.5, 5.6 Hz, 1 H), 4.44

(d, J = 11.7 Hz, 1 H), 4.41 (d, J = 11.7 Hz, 1 H), 4.37 (d, J =

11.7 Hz, 1 H), 4.35 (d, J = 11.7 Hz, 1 H), 3.93 (dd, J = 12.9, 5.6 Hz,

1 H), 3.90 (dd, J = 12.9, 5.6 Hz, 1 H), 3.79 (s, 3 H), 3.43 (d, J =

9.2 Hz, 1 H), 3.40 (d, J = 9.2 Hz, 1 H), 3.02 (ddd, J = 10.6, 9.5,

3.7 Hz, 1 H), 2.97 (s, 3 H), 2.96 (s, 3 H), 2.89 (s, 3 H), 2.85 (s, 3

H), 2.56 (dd, J = 14.0, 3.7 Hz, 1 H), 2.47 (d, J = 14.9 Hz, 1 H),

2.37 (dd, J = 14.0, 10.6 Hz, 1 H), 2.32 (d, J = 14.9 Hz, 1 H), 1.07

(s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 172.4 (C), 172.0

(C), 159.2 (C), 138.7 (C), 133.2 (CH), 130.7 (C), 129.5 (CH), 129.4

(CH), 128.4 (CH), 127.7 (CH), 127.6 (CH), 113.8 (CH), 75.5 (CH₂),

73.4 (CH₂), 71.2 (CH₂), 70.3 (CH₂), 55.4 (CH₃), 45.6 (CH), 40.5

(C), 38.2 (CH₃), 37.7 (CH₃), 37.3 (CH₂), 35.6 (CH₃), 35.6 (CH₃),

34.2 (CH₂), 19.7 (CH₃) ppm. HRMS (FAB): calcd. for C₃₀H₄₃N₂O₅

[M + H]⁺511.3172; found 511.3171.

and ¹³C NMR spectroscopic data were recorded at 500 MHz and

125 MHz, respectively. The chemical shifts are reported in ppm

with respect to the solvent signals as internal references [¹H NMR,

CDCl₃(7.26), C₆D₆(7.16), D₂O (4.79); ¹³C NMR, CDCl₃(77.16),

C₆D₆(128.06)]. The signal patterns are indicated as br., broad

peak; s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplet.

Infrared spectroscopic data were recorded with a Bruker ALPHA

FT-IR spectrometer. Mass spectra (EI and FAB) were measured

with a JEOL GC-Mate spectrometer. Mass spectra [ESI-TOF

(time-of-flight)] were measured with a Waters, LCT Premier XE.

Melting points were measured with a Mitamura–Riken micro hot

stage. Optical rotations were measured with a JASCO DIP-370 in-

strument or JASCO P-2100 polarimeter.

General Procedure A for the Sequential Claisen/Claisen Rearrange-

ment. Synthesis of Bis(dimethylamide) 19a: A sealed tube was

charged with (E)-allylic syn-diol 14a (20.0 mg, 55.8 μmol), Me-

C(OMe)₂NMe₂(180 μL, 1.10 mmol), and tert-butylbenzene

(2.0 mL). The solution was heated to 180 °C and stirred for 2 d at

180 °C. After cooling to room temperature, the solution was diluted

with brine (2 mL), and the resulting solution was extracted with

EtOAc (2 mL). The combined organic extracts were washed with

brine (6ϫ2 mL), dried with Na₂SO₄, and concentrated. The resi-

due was purified by silica gel column chromatography (acetone/

hexane, from 1:5 to 1:1) to give bis(dimethylamide) 19a (24.0 mg,

Bis(dimethylamide) 19b: Following general procedure A, (E)-allylic

anti-diol 14d (19.5 mg, 54.4 μmol) afforded bis(dimethylamide) 19b

(23.7 mg, 88%).

Bis(dimethylamide) 19a: Following general procedure A, (Z)-allylic

anti-diol 14e (20.8 mg, 58.0 μmol) afforded bis(dimethylamide) 19a

(23.1 mg, 80%).

Bis(dimethylamide) 19f: Following general procedure A, (E)-trisub-

stituted allylic anti-diol 14f (20.0 mg, 53.7 μmol) afforded bis(di-

methylamide) 19f (22.5 mg, 82%) as a yellow oil. [α]²_D¹= –4.4 (c =

87%) as a yellow oil. [α]²_D⁷= +4.9 (c = 0.64, CHCl ). IR (film): ν

˜

3

= 2928, 2856, 1641, 1513, 1454, 1248, 1032 cm^–1. ¹H NMR

(500 MHz, CDCl₃): δ = 7.32–7.25 (m, 5 H), 7.23 (d, J = 8.6 Hz, 2

H), 6.86 (d, J = 8.6 Hz, 2 H), 5.64 (dd, J = 15.5, 7.6 Hz, 1 H), 5.58

(dt, J = 15.5, 5.1 Hz, 1 H), 4.44 (s, 2 H), 4.38 (s, 2 H), 3.92 (d, J

= 5.1 Hz, 2 H), 3.79 (s, 3 H), 3.51 (dd, J = 9.5, 5.2 Hz, 1 H), 3.47

(dd, J = 9.5, 5.2 Hz, 1 H), 2.97 (s, 3 H), 2.92 (s, 3 H), 2.90 (s, 3 H),

2.88–2.83 (m, 1 H), 2.87 (s, 3 H), 2.55 (dd, J = 15.0, 5.7 Hz, 1 H),

2.46–2.39 (m, 3 H), 2.32 (dd, J = 18.3, 8.9 Hz, 1 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 172.3 (C), 172.0 (C), 159.2 (C), 138.6 (C),

134.4 (CH), 130.6 (C), 129.5 (CH), 128.6 (CH), 128.4 (CH), 127.7

(CH), 127.6 (CH), 113.9 (CH), 73.2 (CH₂), 71.5 (CH₂), 71.1 (CH₂),

70.4 (CH₂), 55.4 (CH₃), 41.3 (CH), 39.0 (CH), 37.6 (CH₃), 37.5

(CH₃), 36.9 (CH₂), 35.64 (CH₃), 35.59 (CH₃), 33.8 (CH₂) ppm.

HRMS (FAB): calcd. for C₂₉H₄₁N₂O₅[M + H]⁺497.3015; found

497.3006.

0.80, CHCl ). IR (film): ν = 2930, 2854, 1642, 1247, 1102 cm^–1. ¹H

˜

3

NMR (500 MHz, CDCl₃): δ = 7.33–7.28 (m, 5 H), 7.24 (d, J =

8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 5.64 (dd, J = 15.5, 9.2 Hz,

1 H), 5.58 (ddd, J = 15.5, 5.4, 5.2 Hz, 1 H), 4.51 (d, J = 12.0 Hz,

1 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.39 (d, J = 11.5 Hz, 1 H), 4.36

(d, J = 11.5 Hz, 1 H), 3.95 (dd, J = 12.6, 5.4 Hz, 1 H), 3.92 (dd, J

= 12.6, 5.2 Hz, 1 H), 3.80 (s, 3 H), 3.55 (d, J = 9.5 Hz, 1 H), 3.43

(d, J = 9.5 Hz, 1 H), 2.97–2.85 (m, 1 H), 2.97 (s, 3 H), 2.92 (s, 3

H), 2.89 (s, 3 H), 2.84 (s, 3 H), 2.55 (dd, J = 13.8, 3.7 Hz, 1 H),

2.49 (d, J = 14.6 Hz, 1 H), 2.35 (dd, J = 13.8, 10.6 Hz, 1 H), 2.34

(d, J = 14.6 Hz, 1 H), 1.00 (s, 3 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 172.4 (C), 172.0 (C), 159.2 (C), 138.7 (C), 133.1 (CH),

130.7 (C), 130.0 (CH), 129.5 (CH), 128.4 (CH), 127.8 (CH), 127.6

(CH), 113.9 (CH), 74.5 (CH₂), 73.4 (CH₂), 71.3 (CH₂), 70.3 (CH₂),

55.4 (CH₃), 45.7 (CH), 40.4 (C), 38.2 (CH₃), 37.7 (CH₃), 37.6

(CH₂), 35.6 (CH₃), 35.6 (CH₃), 34.3 (CH₂), 18.9 (CH₃) ppm.

HRMS (ESI): calcd. for C₃₀H₄₃N₂O₅[M + H]⁺511.3172; found

511.3173.

Bis(dimethylamide) 19b: Following general procedure A, (Z)-allylic

syn-diol 14b (20.0 mg, 55.8 μmol) afforded bis(dimethylamide) 19b

(22.4 mg, 81%) as a yellow oil. [α]²_D⁷= –10.1 (c = 1.18, CHCl₃). IR

(film): ν = 3471, 2928, 2856, 1643, 1513, 1397, 1248, 1104 cm^–1. ¹H

˜

NMR (500 MHz, CDCl₃): δ = 7.32–7.25 (m, 5 H), 7.23 (d, J =

8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.61 (dd, J = 15.5, 7.7 Hz,

1 H), 5.57 (dt, J = 15.5, 4.9 Hz, 1 H), 4.45 (s, 2 H), 4.38 (d, J =

11.7 Hz, 1 H), 4.36 (d, J = 11.7 Hz, 1 H), 3.91 (d, J = 4.9 Hz, 2

H), 3.79 (s, 3 H), 3.49 (dd, J = 9.7, 4.6 Hz, 1 H), 3.47 (dd, J = 9.7,

General Procedure B for the Claisen Rearrangement through the Cy-

clic Orthoamides. Synthesis of Allylic Alcohol 27a from syn-Diol

14a: A sealed tube was charged with (E)-allylic syn-diol 14a

(18.9 mg, 52.7 μmol), MeC(OMe)₂NMe₂(15 μL, 110 μmol), and o-

xylene (2 mL). After this solution was maintained at room tem-

4.6 Hz, 1 H), 2.94 (s, 3 H), 2.92 (s, 3 H), 2.88 (s, 3 H), 2.87 (s, 3 perature for 3 h, molecular sieves (4 Å, 100 mg) were added to the

H), 2.87–2.82 (m, 1 H), 2.53 (dd, J = 14.9, 5.4 Hz, 1 H), 2.42–2.29

solution. The resulting mixture was then heated to 160 °C and

stirred at 160 °C for 4 d. After cooling to room temperature, the

(m, 4 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 172.4 (C), 171.9

(C), 159.2 (C), 138.6 (C), 134.8 (CH), 130.6 (C), 129.5 (CH), 128.7 mixture was filtered through a pad of Celite. This pad was washed

8

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Chirality Transfers through Sequential Sigmatropic Rearrangements

with toluene (10 mL). After concentration, the residue was purified

by silica gel column chromatography (acetone/hexane, from 1:5 to

1:1) to give allylic alcohol 27a (20.5 mg, 91%) as a colorless oil.

14d: A sealed tube was charged with (E)-allylic anti-diol 14d

(19.4 mg, 54.1 μmol), MeC(OMe)₂NMe₂(16 μL, 110 μmol), and o-

xylene (2.0 mL) at room temperature. The solution was heated to

60 °C. After this solution was maintained at 60 °C for 3 h, molecu-

lar sieves (4 Å, 100 mg) were added to the solution. The resulting

mixture was then heated to 160 °C and stirred at 160 °C for 1.5 d.

[α]²_D⁵= –6.8 (c = 1.49, CHCl ). IR (film): ν = 3413, 2933, 2858,

˜

3

1631, 1513, 1240, 1102, 1031 cm^–1. ¹H NMR (500 MHz, CDCl₃):

δ = 7.34–7.28 (m, 5 H), 7.25 (d, J = 8.9 Hz, 2 H), 6.88 (d, J =

8.9 Hz, 2 H), 5.81 (ddd, J = 15.5, 7.7, 1.1 Hz, 1 H), 5.52 (ddd, J = After cooling to room temperature, the mixture was filtered

15.5, 6.3, 0.9 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.49 (s, 2 H),

4.47 (d, J = 12.0 Hz, 1 H), 4.31–4.27 (m, 1 H), 3.81 (s, 3 H), 3.50

(dd, J = 9.2, 5.4 Hz, 1 H), 3.47 (dd, J = 9.5, 3.2 Hz, 1 H), 3.46 (dd,

J = 9.2, 6.0 Hz, 1 H), 3.30 (dd, J = 9.5, 8.3 Hz, 1 H), 3.00–2.97

(m, 1 H), 2.96 (s, 3 H), 2.90 (s, 3 H), 2.58 (dd, J = 15.5, 6.6 Hz, 1

H), 2.44 (br. s, 1 H), 2.33 (dd, J = 15.5, 7.2 Hz, 1 H) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 171.7 (C), 159.5 (C), 138.6 (C), 133.7

(CH), 130.1 (C), 129.6 (CH), 129.5 (CH), 128.4 (CH), 127.71 (CH),

127.66 (CH), 114.0 (CH), 74.1 (CH₂), 73.13 (CH₂), 73.06 (CH₂),

72.9 (CH₂), 71.3 (CH), 55.4 (CH₃), 39.1 (CH), 37.6 (CH₃), 35.6

(CH₃), 35.2 (CH₂) ppm. LRMS (EI): m/z (%) = 427 (1.1) [M]⁺, 336

(2), 318 (4), 276 (10), 232 (11), 200 (15), 180 (11), 168 (57), 135

(41), 121 (100), 105 (26). HRMS (EI): calcd. for C₂₅H₃₃NO₅[M]⁺

427.2359; found 427.2358.

through a pad of Celite. This pad was washed with toluene

(10 mL). After concentration, the residue was purified by silica gel

column chromatography (acetone/hexane, from 1:5 to 1:1) to give

allylic alcohol 27b (19.1 mg, 80%).

Allylic Alcohol 27a: Following general procedure C, (Z)-allylic anti-

diol 14e (21.8 mg, 60.8 μmol) afforded allylic alcohol 27a (21.0 mg,

81%).

Allylic Alcohol 23f: Following general procedure C (except chang-

ing the reaction temperature to 180 °C), (E)-trisubstituted allylic

anti-diol 14f (20.8 mg, 55.8 μmol) afforded allylic alcohol 27f

(20.7 mg, 84%) as a yellow oil. [α]²_D¹= +6.1 (c = 0.70, CHCl₃). IR

(film): ν = 3417, 2928, 2856, 1640, 1513, 1248, 1102 cm^–1. ¹H NMR

˜

(500 MHz, CDCl₃): δ = 7.34–7.27 (m, 5 H), 7.25 (d, J = 8.6 Hz, 2

H), 6.87 (d, J = 8.6 Hz, 2 H), 5.98 (dd, J = 16.0, 0.9 Hz, 1 H), 5.43

(dd, J = 16.0, 6.6 Hz, 1 H), 4.51 (d, J = 12.6 Hz, 1 H), 4.50 (d, J

= 11.7 Hz, 1 H), 4.49 (d, J = 12.6 Hz, 1 H), 4.48 (d, J = 11.7 Hz,

1 H), 4.30 (dddd, J = 8.3, 6.6, 3.2, 0.9 Hz, 1 H), 3.80 (s, 3 H), 3.46

(dd, J = 9.5, 3.2 Hz, 1 H), 3.44 (d, J = 8.9 Hz, 1 H), 3.39 (d, J =

8.9 Hz, 1 H), 3.31 (dd, J = 9.5, 8.3 Hz, 1 H), 2.96 (s, 3 H), 2.87 (s,

3 H), 2.49 (d, J = 14.6 Hz, 1 H), 2.42 (d, J = 14.6 Hz, 1 H), 1.19

(s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.3 (C), 159.5

(C), 138.9 (CH), 138.8 (C), 130.2 (C), 129.6 (CH), 128.4 (CH),

127.6 (CH), 127.6 (CH), 126.4 (CH), 114.0 (CH), 77.2 (CH₂), 74.1

(CH₂), 73.3 (CH₂), 73.1 (CH₂), 71.7 (CH), 55.4 (CH₃), 40.3 (C),

39.6 (CH₂), 38.2 (CH₃), 35.5 (CH₃), 22.4 (CH₃) ppm. LRMS (EI):

m/z (%) = 441 (0.2) [M]⁺, 290 (5), 246 (3), 214 (9), 182 (27), 166

(6), 121 (97), 91 (100), 72 (64). HRMS (EI): calcd. for C₂₆H₃₅NO₅

[M]⁺441.2515; found 441.2520.

Allylic Alcohol 27b: Following general procedure B, (Z)-allylic syn-

diol 14b (20.2 mg, 56.4 μmol) afforded allylic alcohol 27b (21.4 mg,

89%) as a yellow oil. [α]²_D⁵= +7.4 (c = 1.01, CHCl ). IR (film): ν

˜

3

= 3417, 2858, 1633, 1513, 1455, 1400, 1248, 1101 cm^–1. H NMR

1

(500 MHz, CDCl₃): δ = 7.33–7.28 (m, 5 H), 7.25 (d, J = 8.6 Hz, 2

H), 6.87 (d, J = 8.6 Hz, 2 H), 5.79 (dd, J = 15.8, 7.9 Hz, 1 H), 5.52

(dd, J = 15.8, 6.3 Hz, 1 H), 4.49 (d, J = 11.7 Hz, 1 H), 4.48 (s, 2

H), 4.47 (d, J = 11.7 Hz, 1 H), 4.30–4.27 (m, 1 H), 3.80 (s, 3 H),

3.51 (dd, J = 9.3, 5.3 Hz, 1 H), 3.46 (dd, J = 9.3, 3.0 Hz, 1 H), 3.45

(dd, J = 8.9, 6.3 Hz, 1 H), 3.31 (dd, J = 8.9, 8.9 Hz, 1 H), 3.00–

2.93 (m, 1 H), 2.96 (s, 3 H), 2.89 (s, 3 H), 2.60 (br. s, 1 H), 2.59

(dd, J = 15.5, 6.3 Hz, 1 H), 2.30 (dd, J = 15.5, 7.6 Hz, 1 H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 171.7 (C), 159.4 (C), 138.5 (C),

133.4 (CH), 130.1 (C), 129.6 (CH), 129.5 (CH), 128.4 (CH), 127.7

(CH), 127.6 (CH), 114.0 (CH), 74.0 (CH₂), 73.1 (CH₂), 73.0 (CH₂),

72.9 (CH₂), 71.3 (CH), 55.4 (CH₃), 39.0 (CH), 37.5 (CH₃), 35.5

(CH₃), 35.2 (CH₂) ppm. LRMS (EI): m/z (%) = 427 (1.5) [M]⁺, 336

(2), 318 (4), 276 (13), 232 (11), 200 (19), 168 (67), 135 (27), 121

(100), 107 (20). HRMS (EI): calcd. for C₂₅H₃₃NO₅[M]⁺427.2359;

found 427.2359.

General Procedure D for the Overman Rearrangement. Synthesis of

Trichloroacetamide 29a: Trichloroacetonitrile (29 μL, 290 μmol)

was added to a solution of allylic alcohol 27a (62.0 mg, 145 μmol),

DBU (22 μL, 150 μmol), and CH₂Cl₂(30 mL) at 0 °C. This solu-

tion was warmed to room temperature and maintained at room

temperature for 3.5 h. After concentrating the reaction mixture, the

residue was purified by silica gel column chromatography (EtOAc/

hexane, from 1:2 to 1:1 with 1.0% by volume Et₃N) to give tri-

chloroimidate 28a (65.2 mg, 79%) as a colorless oil. [α]²_D⁵= +81.0

Allylic Alcohol 27c: Following general procedure B, (E)-trisubsti-

tuted allylic syn-diol 14c (21.0 mg, 56.4 μmol) afforded allylic

alcohol 27c (23.6 mg, 95%) as a yellow oil. [α]²_D⁵= –13.3 (c = 0.92,

CHCl ). IR (film): ν = 3410, 2933, 2858, 1616, 1513, 1248, 1102,

˜

3

(c = 0.96, CHCl ). IR (film): ν = 2928, 2859, 1642, 1513, 1301,

˜

1032 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.33–7.27 (m, 5 H),

1

3

1248, 1087, 1032 cm^–1. H NMR (500 MHz, CDCl₃): δ = 8.31 (s,

1

7.25 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.99 (dd, J =

16.0, 1.2 Hz, 1 H), 5.43 (dd, J = 16.0, 6.6 Hz, 1 H), 4.50 (s, 2 H),

4.49 (s, 2 H), 4.32–4.29 (m, 1 H), 3.80 (s, 3 H), 3.46 (dd, J = 9.5,

3.2 Hz, 1 H), 3.45 (d, J = 8.9 Hz, 1 H), 3.39 (d, J = 8.9 Hz, 1 H),

3.31 (dd, J = 9.5, 8.6 Hz, 1 H), 2.96 (s, 3 H), 2.88 (s, 3 H), 2.50

(br. s, 1 H), 2.48 (d, J = 14.6 Hz, 1 H), 2.43 (d, J = 14.6 Hz, 1 H),

1.19 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.4 (C),

159.4 (C), 138.9 (C), 138.8 (CH), 130.2 (C), 129.5 (CH), 128.4

(CH), 127.5 (CH), 127.5 (CH), 126.5 (CH), 114.0 (CH), 77.1 (CH₂),

74.1 (CH₂), 73.3 (CH₂), 73.1 (CH₂), 71.6 (CH), 55.4 (CH₃), 40.3

(C), 39.7 (CH₂), 38.2 (CH₃), 35.5 (CH₃), 22.4 (CH₃) ppm. LRMS

(EI): m/z (%) = 441 (1.6) [M]⁺, 380 (4), 354 (6), 290 (33), 246 (22),

214 (34), 182 (87), 166 (17), 120 (100). HRMS (EI): calcd. for

C₂₆H₃₅NO₅[M]⁺441.2515; found 441.2501.

1 H), 7.33–7.27 (m, 5 H), 7.24 (d, J = 8.6 Hz, 2 H), 6.85 (d, J =

8.6 Hz, 2 H), 5.94 (dd, J = 14.6, 7.8 Hz, 1 H), 5.65–5.58 (m, 2 H),

4.53 (d, J = 11.7 Hz, 1 H), 4.50 (d, J = 11.7 Hz, 1 H), 4.47 (s, 2

H), 3.79 (s, 3 H), 3.65 (dd, J = 10.9, 6.3 Hz, 1 H), 3.62 (dd, J =

10.9, 4.0 Hz, 1 H), 3.51 (dd, J = 9.2, 5.3 Hz, 1 H), 3.47 (dd, J =

9.2, 5.7 Hz, 1 H), 3.04–2.98 (m, 1 H), 2.95 (s, 3 H), 2.89 (s, 3 H),

2.56 (dd, J = 15.2, 6.9 Hz, 1 H), 2.33 (dd, J = 15.2, 7.2 Hz, 1

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.6 (C), 161.9 (C),

159.3 (C), 138.6 (C), 135.7 (CH), 130.3 (C), 129.3 (CH), 128.4

(CH), 127.6 (CH), 127.6 (CH), 125.3 (CH), 113.9 (CH), 91.9 (C),

78.2 (CH), 73.1 (CH₂), 73.0 (CH₂), 72.7 (CH₂), 71.2 (CH₂), 55.4

(CH₃), 39.3 (CH), 37.6 (CH₃), 35.6 (CH₃), 34.9 (CH₂) ppm. HRMS

(FAB): calcd. for C₂₇H₃₄³⁵Cl₂³⁷ClN₂O₅[M + H]⁺573.1504; found

573.1509. A sealed tube was charged with trichloroimidate 28a

(53.3 mg, 125 μmol), K₂CO₃(4.40 mg, 31.8 μmol), and o-xylene

(1 mL). The resulting mixture was stirred at 140 °C for 1.5 h and

General Procedure C for the Claisen Rearrangement through the Cy-

clic Orthoamides. Synthesis of Allylic Alcohol 27b from anti-Diol

Eur. J. Org. Chem. 0000, 0–0

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T. Sato, N. Chida et al.

2858, 1658, 1640, 1513, 1248, 1090, 1032 cm^–^{1 1}H NMR

FULL PAPER

then cooled to room temperature. The reaction mixture was diluted

with H₂O (5 mL), and the resulting mixture was extracted with

EtOAc (2ϫ10 mL). The combined organic extracts were washed

with brine (2ϫ10 mL), dried with Na₂SO₄, and concentrated. The

residue was purified by silica gel column chromatography (EtOAc/

hexane, 1:2) to give trichloroacetamide 29a (44.8 mg, 84%) as a

.

(500 MHz, CDCl₃): δ = 8.32 (s, 1 H), 7.33–7.27 (m, 5 H), 7.24 (d,

J = 8.9 Hz, 2 H), 6.85 (d, J = 8.9 Hz, 2 H), 6.10 (dd, J = 16.0,

0.9 Hz, 1 H), 5.61 (dddd, J = 6.3, 6.3, 4.3, 0.9 Hz, 1 H), 5.54 (dd,

J = 16.0, 6.3 Hz, 1 H), 4.53 (d, J = 11.7 Hz, 1 H), 4.50 (d, J =

11.7 Hz, 1 H), 4.49 (s, 2 H), 3.79 (s, 3 H), 3.65 (dd, J = 10.9, 6.3 Hz,

1 H), 3.62 (dd, J = 10.9, 4.3 Hz, 1 H), 3.44 (d, J = 8.9 Hz, 1 H),

colorless oil. [α]²_D⁵= –2.2 (c = 0.75, CHCl ). IR (film): ν = 2859,

˜

3

2358, 2342, 1712, 1631, 1513, 1402, 1248, 1100 cm^{–1 1}H NMR 3.41 (d, J = 8.9 Hz, 1 H), 2.95 (s, 3 H), 2.87 (s, 3 H), 2.51 (d, J =

.

(500 MHz, CDCl₃): δ = 8.60 (d, J = 8.0 Hz, 1 H), 7.35–7.28 (m, 5

H), 7.24 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.80 (dtd,

J = 15.5, 5.4, 1.0 Hz, 1 H), 5.61 (ddt, J = 15.5, 7.2, 1.4 Hz, 1 H),

14.3 Hz, 1 H), 2.41 (d, J = 14.3 Hz, 1 H), 1.20 (s, 3 H) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 171.1 (C), 162.0 (C), 159.3 (C), 140.4

(CH), 138.8 (C), 130.3 (C), 129.3 (CH), 128.4 (CH), 127.51 (CH),

4.45 (d, J = 11.7 Hz, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.45–4.41 127.47 (CH), 122.5 (CH), 113.9 (CH), 91.9 (C), 78.4 (CH), 77.1

(m, 1 H), 4.42 (s, 2 H), 3.98 (dd, J = 5.4, 1.4 Hz, 2 H), 3.80 (s, 3 (CH₂), 73.3 (CH₂), 73.0 (CH₂), 71.3 (CH₂), 55.4 (CH₃), 40.6 (C),

H), 3.56 (dd, J = 9.2, 5.4 Hz, 1 H), 3.51 (dd, J = 9.2, 6.9 Hz, 1 H),

2.97 (s, 3 H), 2.93 (s, 3 H), 2.64 (ddddd, J = 6.9, 6.9, 6.9, 5.4,

5.4 Hz, 1 H), 2.43 (dd, J = 16.6, 5.4 Hz, 1 H), 2.39 (dd, J = 16.6,

6.9 Hz, 1 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.9 (C),

39.4 (CH₂), 38.3 (CH₃), 35.5 (CH₃), 22.3 (CH₃) ppm. HRMS

(FAB): calcd. for C₂₈H₃₆Cl₃N₂O₅[M + H]⁺585.1690; found

585.1678. Data for trichloroacetamide 29c; colorless oil; [α]²_D⁵

=

–2.0 (c = 0.27, CHCl ). IR (film): ν = 2919, 2850, 2362, 1713, 1635,

˜

3

161.5 (C), 159.4 (C), 137.7 (C), 130.6 (CH), 130.3 (C), 129.5 (CH), 1513, 1457, 1248, 1096, 1076 cm^–1. ¹H NMR (500 MHz, CDCl₃):

128.6 (CH), 128.6 (CH), 128.2 (CH), 128.1 (CH), 113.9 (CH), 93.1 δ = 9.54 (d, J = 7.7 Hz, 1 H), 7.34–7.27 (m, 5 H), 7.25 (d, J =

(C), 73.7 (CH₂), 71.9 (CH₂), 71.1 (CH₂), 69.5 (CH₂), 55.4 (CH), 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.83 (dtd, J = 15.5, 5.4,

55.3 (CH₃), 38.6 (CH), 37.5 (CH₃), 35.9 (CH₃), 33.2 (CH₂) ppm.

HRMS (FAB): calcd. for C₂₇H₃₄³⁵Cl₂³⁷ClN₂O₅[M + H]⁺573.1504;

found 573.1509.

0.6 Hz, 1 H), 5.74 (dd, J = 15.5, 7.7 Hz, 1 H), 4.48 (d, J = 11.5 Hz,

1 H), 4.43 (d, J = 11.5 Hz, 1 H), 4.42 (s, 2 H), 4.39 (dd, J = 7.7,

7.7 Hz, 1 H), 4.00 (d, J = 5.4 Hz, 2 H), 3.80 (s, 3 H), 3.65 (d, J =

9.2 Hz, 1 H), 3.49 (d, J = 9.2 Hz, 1 H), 2.98 (s, 3 H), 2.92 (s, 3 H),

2.47 (d, J = 15.5 Hz, 1 H), 2.26 (d, J = 15.5 Hz, 1 H), 1.19 (s, 3

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.8 (C), 161.5 (C),

159.4 (C), 138.0 (C), 131.1 (CH), 130.4 (C), 129.5 (CH), 128.5

(CH), 128.2 (CH), 128.0 (CH), 127.5 (CH), 113.9 (CH), 93.4 (C),

74.8 (CH₂), 74.0 (CH₂), 71.9 (CH₂), 69.7 (CH₂), 59.1 (CH), 55.4

(CH₃), 41.4 (C), 38.4 (CH₃), 37.3 (CH₂), 35.9 (CH₃), 23.3

(CH₃) ppm. HRMS (FAB): calcd. for C₂₈H₃₆³⁵Cl³⁷Cl₂N₂O₅[M +

H]⁺589.1631; found 589.1640.

Trichloroacetamide 29b: Following general procedure D, allylic

alcohol 27b (72.6 mg, 170 μmol) afforded trichloroacetamide 29b

in 2 steps (75.3 mg, 81% for 2 steps). Data for trichloroimidate

28b; colorless oil; [α]²_D⁵= –5.8 (c = 1.73, CHCl ). IR (film): ν =

˜

3

2932, 2860, 1645, 1513, 1398, 1248, 1085 cm^–1

.

¹H NMR

(500 MHz, CDCl₃): δ = 8.32 (s, 1 H), 7.33–7.27 (m, 5 H), 7.24 (d,

J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.93 (dd, J = 14.3,

7.7 Hz, 1 H), 5.63 (dd, J = 14.3, 6.3 Hz, 1 H), 5.62–5.59 (m, 1 H),

4.53 (d, J = 11.7 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.49 (d, J =

12.0 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 3.80 (s, 3 H), 3.66 (dd,

J = 10.9, 6.6 Hz, 1 H), 3.62 (dd, J = 10.9, 3.7 Hz, 1 H), 3.51 (dd,

J = 9.4, 5.3 Hz, 1 H), 3.47 (dd, J = 9.4, 5.7 Hz, 1 H), 3.04–2.98

(m, 1 H), 2.95 (s, 3 H), 2.89 (s, 3 H), 2.56 (dd, J = 15.2, 6.9 Hz, 1

H), 2.32 (dd, J = 15.2, 6.9 Hz, 1 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 171.5 (C), 161.9 (C), 159.3 (C), 138.6 (C), 135.7 (CH),

130.3 (C), 129.3 (CH), 128.4 (CH), 127.6 (CH), 127.6 (CH), 125.3

(CH), 113.9 (CH), 91.9 (C), 78.1 (CH), 73.1 (CH₂), 73.0 (CH₂),

72.7 (CH₂), 71.2 (CH₂), 55.4 (CH₃), 39.2 (CH), 37.5 (CH₃), 35.6

(CH₃), 34.9 (CH₂) ppm. HRMS (FAB): calcd. for C₂₇H₃₄Cl₃N₂O₅

[M + H]⁺571.1534; found 571.1554. Data for trichloroacetamide

Trichloroacetamide 29f: Following general procedure D, allylic

alcohol 27f (15.4 mg, 34.9 μmol) afforded trichloroacetamide 29f

in 2 steps (14.9 mg, 61% for 2 steps). Data for trichloroimidate 28f;

yellow oil; [α]²_D¹= –5.5 (c = 1.61, CHCl ). IR (film): ν = 2931, 2858,

˜

3

1641, 1513, 1248, 1089 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ =

8.32 (s, 1 H), 7.35–7.27 (m, 5 H), 7.25 (d, J = 8.6 Hz, 2 H), 6.85

(d, J = 8.6 Hz, 2 H), 6.09 (dd, J = 16.0, 0.6 Hz, 1 H), 5.64 (dddd,

J = 6.9, 6.3, 4.0, 0.6, Hz, 1 H), 5.54 (dd, J = 16.0, 6.3 Hz, 1 H),

4.53 (d, J = 11.7 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.51 (d, J =

12.6 Hz, 1 H), 4.48 (d, J = 12.6 Hz, 1 H), 3.79 (s, 3 H), 3.66 (dd,

J = 10.9, 6.9 Hz, 1 H), 3.62 (dd, J = 10.9, 4.0 Hz, 1 H), 3.45 (d, J

= 8.9 Hz, 1 H), 3.41 (d, J = 8.9 Hz, 1 H), 2.93 (s, 3 H), 2.87 (s, 3

H), 2.49 (d, J = 14.3 Hz, 1 H), 2.41 (d, J = 14.3 Hz, 1 H), 1.19 (s,

3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.1 (C), 161.9 (C),

159.3 (C), 140.6 (CH), 138.8 (C), 130.4 (C), 129.3 (CH), 128.4

(CH), 127.5 (CH), 127.5 (CH), 122.4 (CH), 113.9 (CH), 91.9 (C),

78.4 (CH), 77.0 (CH₂), 73.3 (CH₂), 73.0 (CH₂), 71.3 (CH₂), 55.4

(CH₃), 40.5 (C), 39.4 (CH₂), 38.3 (CH₃), 35.5 (CH₃), 22.4

(CH₃) ppm. HRMS (ESI): calcd. for C₂₈H₃₅³⁵Cl₃N₂O₅Na [M +

Na]⁺607.1509; found 607.1506. Data for trichloroacetamide 29f;

29b; colorless oil; [α]²_D⁵= –4.3 (c = 0.42, CHCl ). IR (film): ν =

˜

3

2929, 2858, 1715, 1639, 1513, 1248, 1099, 1034 cm^–1

.

¹H NMR

(500 MHz, CDCl₃): δ = 8.46 (d, J = 8.0 Hz, 1 H), 7.35–7.27 (m, 5

H), 7.25 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.73 (dt,

J = 15.8, 4.3 Hz, 1 H), 5.68 (dd, J = 15.8, 4.0 Hz, 1 H), 4.59–4.56

(m, 1 H), 4.46 (d, J = 11.2 Hz, 1 H), 4.42 (s, 2 H), 4.41 (d, J =

11.2 Hz, 1 H), 3.99 (d, J = 4.3 Hz, 2 H), 3.81 (dd, J = 9.6, 3.2 Hz,

1 H), 3.81 (s, 3 H), 3.58 (dd, J = 9.6, 2.4 Hz, 1 H), 2.96 (s, 3 H),

2.94 (s, 3 H), 2.60 (dd, J = 14.4, 7.2 Hz, 1 H), 2.58–2.55 (m, 1 H),

2.42 (dd, J = 14.4, 4.3 Hz, 1 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 171.3 (C), 161.8 (C), 159.4 (C), 137.3 (C), 130.4 (C),

129.6 (CH), 129.5 (CH), 128.7 (CH), 128.6 (CH), 128.6 (CH), 128.3

(CH), 114.0 (CH), 93.1 (C), 74.2 (CH₂), 71.9 (CH₂), 70.7 (CH₂),

69.6 (CH₂), 55.5 (CH), 55.4 (CH₃), 38.6 (CH), 37.4 (CH₃), 35.8

(CH₃), 32.3 (CH₂) ppm. HRMS (FAB): calcd. for C₂₇H₃₄Cl₃N₂O₅

[M + H]⁺571.1534; found 571.1545.

yellow oil; [α]¹_D⁹= +12.3 (c = 0.93, CHCl ). IR (film): ν = 2925,

˜

3

2854, 1711, 1633, 1512, 1247, 822 cm^{–1 1}H NMR (500 MHz,

.

CDCl₃): δ = 8.99 (d, J = 8.6 Hz, 1 H), 7.35–7.27 (m, 5 H), 7.24 (d,

J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.79 (dtd, J = 15.5,

5.2, 0.9 Hz, 1 H), 5.70 (ddt, J = 15.5, 6.9, 1.2 Hz, 1 H), 4.52 (d, J

= 11.2 Hz, 1 H), 4.44 (d, J = 11.2 Hz, 1 H), 4.42 (s, 2 H), 4.39

(ddd, J = 8.6, 6.9, 0.9 Hz, 1 H), 3.99 (dd, J = 5.2, 1.2 Hz, 2 H),

3.80 (s, 3 H), 3.63 (d, J = 9.2 Hz, 1 H), 3.43 (d, J = 9.2 Hz, 1 H),

3.00 (s, 3 H), 2.94 (s, 3 H), 2.65 (d, J = 15.5 Hz, 1 H), 2.36 (d, J =

15.5 Hz, 1 H), 1.10 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ

= 171.6 (C), 161.5 (C), 159.4 (C), 137.6 (C), 130.9 (CH), 130.4 (C),

Trichloroacetamide 29c: Following the general procedure D, allylic

alcohol 27c (15.4 mg, 34.9 μmol) afforded trichloroacetamide 29c

in 2 steps (14.9 mg, 73% for 2 steps). Data for trichloroimidate 28c;

colorless oil; [α]²_D⁵= –24.1 (c = 0.80, CHCl ). IR (film): ν = 2930,

˜

3

10

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Chirality Transfers through Sequential Sigmatropic Rearrangements

129.5 (CH), 128.6 (CH), 128.5 (CH), 128.2 (CH), 127.4 (CH), 114.0 saturated aqueous NH₄Cl/28% aqueous NH₃(2:1, 3.0 mL). The

(CH), 93.3 (C), 75.5 (CH₂), 74.1 (CH₂), 71.8 (CH₂), 69.6 (CH₂), resulting mixture was extracted with EtOAc (2ϫ2.0 mL). The com-

59.9 (CH), 55.4 (CH₃), 41.2 (C), 38.2 (CH₃), 35.9 (CH₂), 35.8 bined organic extracts were washed with HCl (1 m aqueous solu-

(CH₃), 20.1 (CH₃) ppm. HRMS (ESI): calcd. for C₂₈H₃₆³⁵Cl₃N₂O₅tion, 2.0 mL), saturated aqueous NaHCO₃(4.0 mL), and brine

[M + H]⁺585.1690; found 585.1693.

(10 mL) and then dried with Na₂SO₄. After concentrating the or-

ganic layer, the residue was purified by silica gel column

chromatography (EtOAc/hexane, 1:7) to give ethyl ester 44 (170 mg,

86%) as a colorless oil. [α]²_D⁶= +21.1 (c = 0.99, CHCl₃). IR (film):

Mesylate 43: Chloromethyl methyl ether (9.7 mL, 130 mmol) was

added to a solution of diol 42 (16.6 g, 63.6 mmol), 2,6-lutidine

(15 mL, 130 mmol), and CH₂Cl₂(350 mL) at 0 °C. This solution

was maintained at 0 °C for 15 min and then warmed to room tem-

perature. The solution was maintained at room temperature for

12 h and then quenched with H₂O (200 mL). The resulting mixture

was extracted with CHCl₃(2ϫ100 mL). The combined organic ex-

tracts were washed with brine (200 mL), dried with Na₂SO₄, and

concentrated. The residue was purified by silica gel column

chromatography (EtOAc/hexane, from 1:3 to 1:2) to give the MOM

ν = 2985, 2936, 2887, 1734, 1216, 1153, 1045 cm^{–1 1}H NMR

.

˜

(500 MHz, CDCl₃): δ = 6.02 (ddd, J = 15.5, 8.3, 0.9 Hz, 1 H), 5.56

(ddd, J = 15.5, 7.7, 0.9 Hz, 1 H), 4.92 (dq, J = 2.2, 1.2 Hz, 1 H),

4.88–4.87 (m, 1 H), 4.66 (ddd, J = 7.7, 6.6, 0.9 Hz, 1 H), 4.62 (s, 2

H), 4.36 (ddd, J = 6.6, 6.6, 5.4 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 2 H),

3.71 (dd, J = 8.3, 0.9 Hz, 1 H), 3.51–3.46 (m, 1 H), 3.36 (s, 3 H),

1.76–1.75 (m, 3 H), 1.50 (s, 3 H), 1.38 (s, 3 H), 1.26 (t, J = 7.2 Hz,

3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.8 (C), 141.9 (C),

130.9 (CH), 128.3 (CH), 114.0 (CH₂), 109.2 (C), 96.8 (CH₂), 77.7

(CH), 77.2 (CH), 67.2 (CH₂), 61.1 (CH₂), 56.1 (CH), 55.5 (CH₃),

28.0 (CH₃), 25.5 (CH₃), 20.9 (CH₃), 14.3 (CH₃) ppm. HRMS

(FAB): calcd. for C₁₇H₂₉O₆[M + H]⁺329.1964; found 329.1957.

ether (14.5 g, 75%) as colorless crystals, m.p. 38–42 °C. [α]²_D⁶

=

–13.5 (c = 0.90, CHCl ). IR (film): ν = 3469, 2985, 1720, 1041 cm^–1.

˜

3

¹H NMR (500 MHz, CDCl₃): δ = 6.97 (dd, J = 15.8, 4.3 Hz, 1 H),

6.16 (dd, J = 15.8, 1.8 Hz, 1 H), 4.68 (s, 2 H), 4.44–4.40 (m, 1 H),

4.42 (ddd, J = 6.8, 6.0, 5.7 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.19

(dd, J = 6.8, 3.0 Hz, 1 H), 3.85 (dd, J = 10.6, 5.7 Hz, 1 H), 3.80

(dd, J = 10.6, 6.0 Hz, 1 H), 3.39 (s, 3 H), 2.74 (d, J = 6.9 Hz, 1 H),

1.51 (s, 3 H), 1.38 (s, 3 H), 1.29 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 166.4 (C), 146.7 (CH), 122.3 (CH), 109.0

(C), 97.0 (CH₂), 78.5 (CH), 75.9 (CH), 69.0 (CH), 66.3 (CH₂), 60.6

(CH₂), 55.8 (CH₃), 27.1 (CH₃), 24.8 (CH₃), 14.4 (CH₃) ppm.

HRMS (FAB): calcd. for C₁₄H₂₅O₇[M + H]⁺305.1600; found

305.1603. Methanesulfonyl chloride (3.2 mL, 42 mmol) was added

dropwise to a solution of the MOM ether (8.49 g, 27.9 mmol),

Et₃N (5.8 mL, 42 mmol), and CH₂Cl₂(150 mL) at 0 °C. This solu-

tion was maintained at 0 °C for 1 h and then quenched with H₂O

(30 mL). The resulting mixture was extracted with CHCl₃

(2 ϫ 10 mL). The combined organic extracts were washed with

brine (30 mL), dried with Na₂SO₄, and concentrated. The residue

was purified by silica gel column chromatography (EtOAc/hexane,

from 1:2 to 1:1) to give mesylate 43 (10.6 g, 100%) as a colorless

(E)-Allylic anti-Diol 45: Lithium aluminum hydride (198 mg,

5.20 mmol) was added to a solution of ethyl ester 44 (1.55 g,

4.73 mmol) and THF (40 mL) at 0 °C. The resulting mixture was

stirred for 20 min at 0 °C and then quenched with HCl (1 m aque-

ous solution, 20 mL). The resulting mixture was extracted with

EtOAc (2 ϫ 20 mL), and the combined organic extracts were

washed with brine (30 mL), dried with Na₂SO₄, and concentrated.

The residue was purified by silica gel column chromatography

(EtOAc/hexane, from 1:2 to 1:1) to give the corresponding alcohol

(1.31 g, 97%) as a colorless oil. [α]²_D⁶= +15.3 (c = 0.64, CHCl₃).

IR (film): ν = 3446, 1647, 1541, 1374, 1216, 1152, 1044 cm^–1. ¹H

˜

NMR (500 MHz, CDCl₃): δ = 5.74 (dd, J = 15.5, 7.8 Hz, 1 H),

5.59 (dd, J = 15.5, 7.4 Hz, 1 H), 4.93–4.91 (m, 1 H), 4.82–4.81 (m,

1 H), 4.64 (dd, J = 7.4, 6.6 Hz, 1 H), 4.63 (s, 2 H), 4.33 (ddd, J =

6.6, 6.6, 5.2 Hz, 1 H), 3.70–3.60 (m, 2 H), 3.54 (dd, J = 10.6,

5.2 Hz, 1 H), 3.50 (dd, J = 10.6, 6.6 Hz, 1 H), 3.36 (s, 3 H), 2.95

(ddd, J = 7.8, 6.8, 6.3 Hz, 1 H), 1.74–1.73 (m, 3 H), 1.61–1.57 (m,

1 H), 1.49 (s, 3 H), 1.38 (s, 3 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 144.2 (C), 133.5 (CH), 127.7 (CH), 112.9 (CH₂), 109.0

(C), 96.9 (CH₂), 78.0 (CH), 77.1 (CH), 67.1 (CH₂), 63.7 (CH₂),

55.5 (CH₃), 52.5 (CH), 28.0 (CH₃), 25.5 (CH₃), 21.0 (CH₃) ppm.

HRMS (FAB): calcd. for C₁₅H₂₇O₅[M + H]⁺287.1858; found

287.1867. A solution of the above alcohol (660 mg, 2.30 mmol) and

DMF (13 mL) was added to a mixture of NaH (60% in oil, 180 mg,

4.6 mmol) and THF (13 mL) at 0 °C. After the mixture was stirred

at 0 °C for 30 min, a solution of p-methoxybenzyl bromide (500 μL,

3.5 mmol) and DMF (13 mL) was added to the mixture at 0 °C.

The resulting mixture was stirred at 0 °C for 2 h and then warmed

to room temperature. After stirring for 1 h at room temperature,

the reaction mixture was quenched with H₂O (20 mL), and the re-

sulting mixture was extracted with EtOAc (2ϫ20 mL). The com-

bined organic extracts were washed with brine (3ϫ20 mL), dried

with Na₂SO₄, and concentrated. The residue was filtered through

a pad of silica gel (EtOAc/hexane, 1:7) to give the MPM ether

(1.17 g), which was used in the next reaction without further purifi-

cation. For analytical samples, the crude mixture was purified by

silica gel column chromatography (EtOAc/hexane, 1:10) to afford

the MPM ether as a colorless oil. [α]²_D⁶= +9.0 (c = 1.19, CHCl₃).

oil. [α]²_D⁶= –21.8 (c = 0.77, CHCl ). IR (film): ν = 2987, 2940, 1722,

˜

3

1360, 1176, 1043, 930 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.00

(dd, J = 15.6, 5.6 Hz, 1 H), 6.26 (dd, J = 15.6, 1.6 Hz, 1 H), 5.36

(ddd, J = 7.2, 5.6, 1.6 Hz, 1 H), 4.66 (s, 2 H), 4.36 (ddd, J = 6.0,

6.0, 6.0 Hz, 1 H), 4.25 (dd, J = 7.2, 6.0 Hz, 1 H), 4.21 (q, J =

7.2 Hz, 2 H), 3.75 (dd, J = 10.6, 6.0 Hz, 1 H), 3.67 (dd, J = 10.6,

6.0 Hz, 1 H), 3.39 (s, 3 H), 3.10 (s, 3 H), 1.49 (s, 3 H), 1.37 (s, 3

H), 1.30 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 165.5 (C), 140.0 (CH), 125.9 (CH), 109.7 (C), 97.0 (CH₂), 78.4

(CH), 77.9 (CH), 75.5 (CH), 65.8 (CH₂), 61.1 (CH₂), 55.9 (CH₃),

39.3 (CH₃), 27.4 (CH₃), 25.6 (CH₃), 14.3 (CH₃) ppm. HRMS

(FAB): calcd. for C₁₅H₂₇O₉S [M + H]⁺383.1375; found 383.1366.

Ethyl Ester 44: tert-Butyllithium (1.76 m solution in pentane,

4.8 mL, 8.4 mmol) was added dropwise to a solution of 2-bromo-

propene (370 µL, 4.2 mmol) and THF (freshly distilled from so-

dium/benzophenone, 4.0 mL) at –78 °C. This solution was added

dropwise through a cannula to a stirring mixture at –78 °C of THF

(2.0 mL) and ZnBr₂(471 mg, 2.09 mmol), which was freshly dried

with a heat gun under reduced pressure until ZnBr₂remained as a

liquid. Meanwhile, a mixture of CuCN (94.0 mg, 1.05 mmol) and

LiBr (182 mg, 2.09 mmol) was dried with a heat gun until the mix-

ture became a gray color, and then THF (2.0 mL) was added. The

solution of dialkenylzinc was added dropwise through a cannula to

the stirring mixture of CuCN, LiBr, and THF at –78 °C. To the

solution at –78 °C was added a solution of mesylate 43 (229 mg,

599 µmol) and THF (2.0 mL) through a cannula. The resulting

solution was maintained at –78 °C for 1 h and then quenched with

IR (film): ν = 2936, 2856, 2838, 1613, 1513, 1247, 1113, 1039 cm^–1.

˜

¹H NMR (500 MHz, CDCl₃): δ = 7.24 (d, J = 8.9 Hz, 2 H), 6.87

(d, J = 8.9 Hz, 2 H), 5.73 (ddd, J = 15.5, 7.2, 0.7 Hz, 1 H), 5.50

(ddd, J = 15.5, 7.9, 1.1 Hz, 1 H), 4.85 (dq, J = 1.4, 1.4 Hz, 1 H),

4.78–4.77 (m, 1 H), 4.62–4.59 (m, 1 H), 4.61 (s, 2 H), 4.46 (d, J =

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T. Sato, N. Chida et al.

FULL PAPER

11.7 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 4.33 (ddd, J = 6.6, 6.6,

(CH), 37.5 (CH₃), 36.5 (CH₂), 35.6 (CH₃), 21.3 (CH₃) ppm. HRMS

5.7 Hz, 1 H), 3.80 (s, 3 H), 3.50 (dd, J = 9.2, 7.2 Hz, 1 H), 3.52– (FAB): calcd. for C₂₄H₃₈NO₆[M + H]⁺436.2699; found 436.2694.

3.45 (m, 1 H), 3.46 (dd, J = 9.2, 6.6 Hz, 1 H), 3.35 (s, 3 H), 3.07

Trichloroacetamide 47: Trichloroacetonitrile (630 μL, 6.2 mmol)

(dddd, J = 7.2, 7.2, 6.6, 1.1 Hz, 1 H), 1.69–1.68 (m, 3 H), 1.50 (s,

was added to a solution of allylic alcohol 46 (905 mg, 2.08 mmol),

3 H), 1.37 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 159.3

DBU (930 μL, 6.2 mmol), and CH₂Cl₂(30 mL) at 0 °C. This solu-

(C), 144.7 (C), 134.6 (CH), 130.5 (C), 129.4 (CH), 126.5 (CH),

tion was warmed to room temperature and maintained at room

113.9 (CH), 112.5 (CH₂), 109.0 (C), 96.8 (CH₂), 78.2 (CH), 77.3

temperature for 1 h. The reaction mixture was concentrated, and

(CH), 72.8 (CH₂), 71.2 (CH₂), 67.4 (CH₂), 55.43 (CH₃), 55.38

the residue was purified by silica gel column chromatography

(CH₃), 49.6 (CH), 28.0 (CH₃), 25.5 (CH₃), 20.7 (CH₃) ppm. LRMS

(EtOAc/hexane, 1:1 with 0.5% by volume Et₃N) to give the tri-

(EI): m/z (%) = 406 (4.4) [M]⁺, 391 (23), 376 (13), 361 (31), 348

chloroimidate (1.16 g, 96%) as a yellow oil. [α]²_D⁶= +12.9 (c = 1.16,

(25), 331 (72), 318 (60), 303 (48), 286 (37), 272 (41), 258 (67), 230

CHCl ). IR (film): ν = 2935, 1642, 1513, 1399, 1248, 1036,

˜

3

(100), 189 (94), 181 (47). HRMS (EI): calcd. for C₂₃H₃₄O₆[M]⁺

406.2355; found 406.2358. A solution of the crude MPM ether

(1.17 g) was dissolved in AcOH/H₂O (4:1, 35 mL) at 45 °C. This

solution was maintained at 45 °C for 5 h and then concentrated.

The residue was purified by silica gel column chromatography

(EtOAc/hexane, from 1:1 to 1:2) to give (E)-allylic anti-diol 45

(757 mg, 90% for 2 steps) as a colorless oil. [α]²_D⁶= +10.7 (c = 0.61,

796 cm^–1. H NMR (500 MHz, CDCl₃): δ = 8.29 (s, 1 H), 7.21 (d,

1

J = 8.5 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 5.77 (dd, J = 15.2,

9.5 Hz, 1 H), 5.52 (ddd, J = 7.1, 7.1, 3.6 Hz, 1 H), 5.46 (dd, J =

15.2, 7.1 Hz, 1 H), 4.82 (s, 1 H), 4.71 (s, 1 H), 4.63 (s, 2 H), 4.39

(d, J = 11.7 Hz, 1 H), 4.36 (d, J = 11.7 Hz, 1 H), 3.79 (s, 3 H),

3.71 (dd, J = 11.2, 7.1 Hz, 1 H), 3.64 (dd, J = 11.2, 3.6 Hz, 1 H),

3.46 (dd, J = 9.5, 7.0 Hz, 1 H), 3.44 (dd, J = 9.5, 7.0 Hz, 1 H), 3.34

(s, 3 H), 2.95–2.88 (m, 1 H), 2.91 (s, 3 H), 2.88 (s, 3 H), 2.48 (ddd,

J = 7.0, 7.0, 7.0 Hz, 1 H), 2.46 (dd, J = 15.2, 5.0 Hz, 1 H), 2.30

(dd, J = 15.2, 8.2 Hz, 1 H), 1.63 (s, 3 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 171.6 (C), 161.8 (C), 159.2 (C), 144.4 (C), 137.3 (CH),

130.6 (C), 129.3 (CH), 124.8 (CH), 114.1 (CH₂), 113.8 (CH), 96.7

(CH₂), 91.9 (C), 78.2 (CH), 72.7 (CH₂), 71.1 (CH₂), 68.9 (CH₂),

55.4 (CH₃), 55.4 (CH₃), 50.3 (CH), 39.9 (CH), 37.5 (CH₃), 36.3

(CH₂), 35.6 (CH₃), 21.4 (CH₃) ppm. HRMS (FAB): calcd. for

C₂₆H₃₈³⁵Cl³⁷Cl₂N₂O₆[M + H]⁺583.1737; found 583.1748. A se-

aled tube was charged with the above trichloroimidate (1.16 g,

2.00 mmol), K₂CO₃(1.00 g, 7.24 mmol), and toluene (100 mL).

The reaction mixture was stirred at 120 °C for 17 h, cooled to room

temperature, and then diluted with H₂O (100 mL). The resulting

mixture was extracted with EtOAc (100 mL, 2ϫ20 mL). The com-

bined organic extracts were washed with brine (50 mL), dried with

Na₂SO₄, and concentrated. The residue was purified by silica gel

column chromatography (EtOAc/hexane, 1:2) to give trichloroacet-

amide 47 (840 mg, 73%) as a colorless oil. [α]²_D⁶= +5.2 (c = 0.76,

CHCl ). IR (film): ν = 3423, 2936, 2887, 1514, 1248, 1112,

˜

3

1035 cm^–1. H NMR (500 MHz, CDCl₃): δ = 7.24 (d, J = 8.6 Hz,

1

2 H), 6.87 (d, J = 8.6 Hz, 2 H), 5.73 (ddd, J = 15.6, 7.2, 1.1 Hz, 1

H), 5.59 (ddd, J = 15.6, 5.8, 0.8 Hz, 1 H), 4.84 (dq, J = 1.4, 1.4 Hz,

1 H), 4.78–4.77 (m, 1 H), 4.63 (s, 2 H), 4.45 (s, 2 H), 4.24–4.21 (m,

1 H), 3.80 (s, 3 H), 3.78–3.75 (m, 1 H), 3.68 (dd, J = 10.6, 3.4 Hz,

1 H), 3.60 (dd, J = 10.6, 6.6 Hz, 1 H), 3.52 (dd, J = 9.2, 7.2 Hz, 1

H), 3.46 (dd, J = 9.2, 7.2 Hz, 1 H), 3.37 (s, 3 H), 3.07 (dddd, J =

7.2, 7.2, 7.2, 0.8 Hz, 1 H), 2.80 (d, J = 4.6 Hz, 1 H), 2.34 (d, J =

5.8 Hz, 1 H), 1.70–1.69 (m, 3 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 159.3 (C), 144.8 (C), 133.2 (CH), 130.4 (C), 129.7

(CH), 129.5 (CH), 113.9 (CH), 112.3 (CH₂), 97.3 (CH₂), 73.8 (CH),

72.9 (CH), 72.8 (CH₂), 71.4 (CH₂), 69.7 (CH₂), 55.7 (CH₃), 55.4

(CH₃), 49.7 (CH), 20.8 (CH₃) ppm. LRMS (EI): m/z (%) = 366

(2.7) [M]⁺, 366 (3), 348 (11), 321 (41), 303 (37), 261 (39), 231 (100),

213 (20), 202 (18), 189 (23), 166 (22), 150 (27). HRMS (EI): calcd.

for C₂₀H₃₀O₆[M]⁺366.2042; found 366.2036.

Allylic Alcohol 46: A sealed portable reactor (TVS-1, φ

4.5 cmϫ21 cm, Taiatsu Techno Co., Inc.) with an internal ther-

mometer and pressure gauge was charged with (E)-allylic anti-diol

45 (1.39 g, 3.79 mmol), MeC(OMe)₂NMe₂(1.1 mL, 7.6 mmol), and

toluene (95 mL). After this solution was maintained at room tem-

perature for 5 h, molecular sieves (4 Å, 7.00 g) were added. The

sealed vessel was heated to 135 °C (internal temperature, 1.8 atm)

with an oil bath and stirred at 135 °C for 8.5 d. After cooling to

room temperature, the mixture was filtered through a pad of Celite.

This pad was washed with toluene (100 mL), and the resulting fil-

trate was concentrated. The residue was purified by silica gel col-

umn chromatography (acetone/hexane, 1:1) to give allylic alcohol

46 (1.15 g, 70%) as a yellow oil. [α]²_D⁶= –6.3 (c = 0.80, CHCl₃). IR

CHCl ). IR (film): ν = 2935, 1710, 1632, 1513, 1248, 1037,

˜

3

823 cm^–1. H NMR (500 MHz, CDCl₃): δ = 9.01 (d, J = 8.0 Hz, 1

1

H), 7.22 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 5.73–5.65

(m, 2 H), 4.90 (dq, J = 1.4, 1.4 Hz, 1 H), 4.77–4.76 (m, 1 H), 4.61

(s, 2 H), 4.60–4.57 (m, 1 H), 4.46 (d, J = 11.6 Hz, 1 H), 4.41 (d, J

= 11.6 Hz, 1 H), 4.08–4.07 (m, 2 H), 3.80 (s, 3 H), 3.51 (dd, J =

9.7, 4.4 Hz, 1 H), 3.48 (dd, J = 9.7, 6.3 Hz, 1 H), 3.35 (s, 3 H), 2.93

(s, 3 H), 2.89 (s, 3 H), 2.60 (dddd, J = 10.9, 8.3, 2.6, 2.6 Hz, 1 H),

2.49 (dd, J = 16.0, 2.6 Hz, 1 H), 2.39–2.36 (m, 1 H), 2.37 (dd, J =

16.0, 10.9 Hz, 1 H), 1.77–1.76 (m, 3 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 172.9 (C), 161.5 (C), 159.5 (C), 145.6 (C), 129.8 (C),

129.6 (CH), 128.9 (CH), 128.6 (CH), 113.9 (CH), 113.8 (CH₂), 95.7

(CH₂), 93.3 (C), 73.1 (CH₂), 71.3 (CH₂), 67.3 (CH₂), 55.4 (CH₃),

55.4 (CH₃), 54.0 (CH), 47.8 (CH), 39.5 (CH), 37.4 (CH₃), 35.9

(CH₃), 31.6 (CH₂), 21.0 (CH₃) ppm. LRMS (EI): m/z (%) = 578

(1.1) [M]⁺, 517 (19), 406 (22), 381 (23), 344 (10), 234 (30), 219 (25),

166 (100), 154 (30), 135 (70), 121 (100). HRMS (EI): calcd. for

C₂₆H₃₇³⁵Cl₂³⁷ClN₂O₆[M]⁺580.1688; found 580.1690.

(film): ν = 3417, 2935, 1630, 1513, 1248, 1113, 1035 cm^–1. ¹H NMR

˜

(500 MHz, CDCl₃): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.86 (d, J =

8.6 Hz, 2 H), 5.65 (ddd, J = 15.5, 9.2, 1.2 Hz, 1 H), 5.42 (ddd, J =

15.5, 5.7, 0.6 Hz, 1 H), 4.84 (dq, J = 1.4, 1.4 Hz, 1 H), 4.73–4.72

(m, 1 H), 4.65 (d, J = 6.6 Hz, 1 H), 4.64 (d, J = 6.6 Hz, 1 H), 4.42

(d, J = 11.7 Hz, 1 H), 4.39 (d, J = 11.7 Hz, 1 H), 4.25–4.21 (m, 1

H), 3.79 (s, 3 H), 3.56 (dd, J = 10.5, 3.2 Hz, 1 H), 3.49 (dd, J = Aldehyde 48: HCl (6 m aqueous solution, 20 mL, 120 mmol) was

9.5, 6.3 Hz, 1 H), 3.47 (dd, J = 9.5, 6.7 Hz, 1 H), 3.38 (s, 3 H), 3.33

(dd, J = 10.5, 8.0 Hz, 1 H), 2.92 (s, 3 H), 2.89 (s, 3 H), 2.91–2.86

(m, 1 H), 2.57 (d, J = 3.2 Hz, 1 H), 2.49 (dd, J = 15.0, 5.5 Hz, 1

H), 2.49–2.45 (m, 1 H), 2.31 (dd, J = 15.0, 8.3 Hz, 1 H), 1.67–1.66

(m, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.8 (C), 159.2

added dropwise to a solution of trichloroacetamide 47 (1.15 g,

1.98 mmol) and THF (40 mL) at 0 °C. This solution was warmed

to room temperature and maintained at room temperature for 8 h.

The reaction mixture was diluted with brine (30 mL), and the re-

sulting mixture was extracted with EtOAc (2ϫ40 mL). The com-

(C), 144.8 (C), 133.9 (CH), 130.6 (C), 129.4 (CH), 129.2 (CH), bined organic extracts were washed with brine (30 mL), dried with

113.82 (CH), 113.78 (CH₂), 97.1 (CH₂), 73.0 (CH₂), 72.7 (CH₂),

71.3 (CH), 71.0 (CH₂), 55.6 (CH₃), 55.4 (CH₃), 50.5 (CH), 39.5

Na₂SO₄, and concentrated. The residue was purified by silica gel

column chromatography (EtOAc/hexane, from 1:2 to 1:1) to give

12

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Chirality Transfers through Sequential Sigmatropic Rearrangements

the primary alcohol (959 mg, 90%) as a colorless oil. [α]²_D⁶= +10.8

10.9, 6.3, 2.5, 2.5 Hz, 1 H), 2.94 (s, 3 H), 2.87 (s, 3 H), 2.49 (dd, J

= 16.6, 2.5 Hz, 1 H), 2.49 (dt, J = 6.3, 6.3 Hz, 1 H), 2.34 (dd, J =

(c = 1.21, CHCl ). IR (film): ν = 3249, 2935, 1708, 1627, 1513,

˜

3

1248, 1088, 823 cm^–1. H NMR (500 MHz, CDCl₃): δ = 9.04 (d, J 16.6, 10.9 Hz, 1 H), 1.74–1.73 (m, 3 H) ppm. ¹³C NMR (125 MHz,

1

= 7.5 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 CDCl₃): δ = 171.8 (C), 170.9 (C), 162.5 (C), 159.5 (C), 145.1 (C),

H), 5.79–5.74 (m, 1 H), 5.68 (dddd, J = 15.5, 5.4, 2.6, 1.4 Hz, 1

129.6 (C), 129.6 (CH), 114.0 (CH), 113.5 (CH₂), 92.8 (C), 73.1

H), 4.90 (s, 1 H), 4.77 (s, 1 H), 4.59–4.56 (m, 1 H), 4.46 (d, J = (CH₂), 70.6 (CH₂), 56.2 (CH), 55.4 (CH₃), 52.4 (CH₃), 46.9 (CH),

11.7 Hz, 1 H), 4.41 (d, J = 11.7 Hz, 1 H), 4.18–4.15 (m, 2 H), 3.80

(s, 3 H), 3.51 (dd, J = 9.7, 4.7 Hz, 1 H), 3.48 (dd, J = 9.7, 6.4 Hz,

38.0 (CH), 37.3 (CH₃), 35.9 (CH₃), 31.0 (CH₂), 21.5 (CH₃) ppm.

LRMS (EI): m/z (%) = 536 (3.6) [M]⁺, 500 (3), 415 (11), 399 (16),

1 H), 2.93 (s, 3 H), 2.89 (s, 3 H), 2.59 (dddd, J = 10.6, 8.3, 2.5, 364 (83), 331 (15), 304 (30), 286 (23), 274 (13), 168 (100), 135 (33),

2.5 Hz, 1 H), 2.51 (dd, J = 15.8, 2.5 Hz, 1 H), 2.38–2.35 (m, 1 H), 121 (100). HRMS (EI): calcd. for C₂₃H₃₁Cl₃N₂O₆[M]⁺536.1248;

2.36 (dd, J = 15.8, 10.6 Hz, 1 H), 1.76 (s, 3 H), 1.60–1.57 (m, 1

H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 173.1 (C), 161.6 (C),

159.5 (C), 145.6 (C), 132.0 (CH), 129.8 (C), 129.6 (CH), 126.7

(CH), 114.0 (CH), 113.9 (CH₂), 93.3 (C), 73.1 (CH₂), 71.3 (CH₂),

63.0 (CH₂), 55.4 (CH₃), 54.1 (CH), 47.9 (CH), 39.4 (CH), 37.5

(CH₃), 36.0 (CH₃), 31.5 (CH₂), 21.0 (CH₃) ppm. HRMS (FAB):

calcd. for C₂₄H₃₄Cl₃N₂O₅[M + H]⁺535.1534; found 535.1530. N-

Methylmorpholine-N-oxide (49.1 mg, 419 μmol) was divided into

four portions (13.1 mg, 13.1 mg, 13.1 mg, and 9.8 mg). Each por-

tion was dissolved in CH₂Cl₂(130 μL), and the resulting solutions

were added every 17 h to a solution of the primary alcohol (150 mg,

280 μmol), osmium tetroxide (0.1 m solution in CH₂Cl₂, 140 μL,

14 μmol), and CH₂Cl₂(19 mL) at –20 °C. After stirring for 15 h at

–20 °C, a solution of lead tetraacetate (248 mg, 560 μmol) and

CH₂Cl₂(500 μL) was added to the solution of the generated diol.

The resulting mixture was stirred at –20 °C for 30 min and then

diluted with H₂O (10 mL). The resulting mixture was extracted

with CHCl₃(2ϫ40 mL), and the combined organic extracts were

washed with brine (20 mL), dried with Na₂SO₄, and concentrated.

The residue was filtered through a pad of silica gel (EtOAc/hexane,

2:1) to give the corresponding aldehyde 48 as a colorless oil, which

was immediately used in the next reaction without further purifica-

found 536.1245.

Kainic Acid (41): Ceric ammonium nitrate (148 mg, 270 μmol) was

added to a solution of methyl ester 49 (48.5 mg, 90.2 μmol) and

MeCN/H₂O (10:1, 4.5 mL) at 0 °C. The resulting mixture was

warmed to room temperature and maintained at room temperature

for 1.5 h. The reaction mixture was diluted with saturated aqueous

NaHCO₃(1 mL) and H₂O (3 mL), and the resulting solution was

extracted with CHCl₃(3ϫ10 mL). The combined organic extracts

were washed with brine (5 mL), dried with Na₂SO₄, and concen-

trated. The residue was purified by silica gel column chromatog-

raphy (EtOAc/hexane, from 1:1 to 3:2) to give the primary alcohol

(34.2 mg, 91%) as a colorless oil. [α]²_D⁶= +6.9 (c = 0.75, CHCl₃).

IR (film): ν = 3211, 2951, 1749, 1710, 1627, 1512, 1208, 827 cm^–1.

˜

¹H NMR (500 MHz, CDCl₃): δ = 9.06 (d, J = 3.0 Hz, 1 H), 5.03

(s, 1 H), 4.85 (s, 1 H), 4.75 (dd, J = 7.6, 3.0 Hz, 1 H), 3.76 (s, 3 H),

3.68 (dd, J = 11.2, 5.6 Hz, 1 H), 3.64 (dd, J = 11.2, 6.3 Hz, 1 H),

3.00 (s, 3 H), 2.97 (s, 3 H), 2.99–2.92 (m, 1 H), 2.49 (dd, J = 16.6,

4.0 Hz, 1 H), 2.44 (dd, J = 16.6, 9.0 Hz, 1 H), 2.43–2.38 (m, 1 H),

1.79 (s, 3 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.7 (C),

171.0 (C), 162.4 (C), 144.2 (C), 114.6 (CH₂), 92.7 (C), 62.0 (CH₂),

56.2 (CH), 52.6 (CH₃), 49.7 (CH), 37.5 (CH₃), 37.2 (CH), 36.1

(CH₃), 31.2 (CH₂), 21.5 (CH₃) ppm. LRMS (EI): m/z (%) = 416

(13.1) [M]⁺, 398 (11), 387 (31), 331 (53), 299 (32), 273 (18), 255

(18), 237 (16), 225 (13), 196 (76), 184 (33). HRMS (EI): calcd. for

C₁₅H₂₃³⁵Cl₂³⁷ClN₂O₅[M]⁺418.0643; found 418.0650. Diethyl azo-

dicarboxylate (2.55 m solution in toluene, 52 μL, 100 μmol) was

added dropwise to a solution of the primary alcohol (28.7 mg,

68.7 mmol), PBu₃(26 μL, 100 μmol), and THF (freshly distilled

from sodium/benzophenone, 2 mL) at 0 °C. This solution was

maintained at 0 °C for 1 h and then quenched with H₂O (3 mL).

The resulting solution was extracted with EtOAc (2ϫ10 mL). The

combined organic extracts were washed with brine (4 mL), dried

with Na₂SO₄, and concentrated. The residue was purified by silica

1

tion. H NMR (500 MHz, CDCl₃): δ = 9.64 (s, 1 H), 8.72 (d, J =

6.9 Hz, 1 H), 7.21 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H),

4.93 (dq, J = 1.4, 1.4 Hz, 1 H), 4.84–4.83 (m, 1 H), 4.67 (dd, J =

6.9, 3.2 Hz, 1 H), 4.44 (d, J = 11.7 Hz, 1 H), 4.41 (d, J = 11.7 Hz,

1 H), 3.80 (s, 3 H), 3.48 (d, J = 5.7 Hz, 2 H), 3.01 (dddd, J = 8.3,

8.3, 4.3, 3.2 Hz, 1 H), 2.92 (s, 3 H), 2.85 (s, 3 H), 2.60 (dt, J = 8.3,

5.7 Hz, 1 H), 2.52 (dd, J = 16.6, 8.3 Hz, 1 H), 2.46 (dd, J = 16.6,

4.3 Hz, 1 H), 1.77–1.76 (m, 3 H) ppm.

Methyl Ester 49: A solution of NaClO₂(76.0 mg, 840 μmol),

NaH₂PO₄(101 mg, 840 μmol), and H₂O (2 mL) was added to a

solution of the crude aldehyde 48, 2-methyl-2-butene (180 μL,

1.7 mmol), and tert-butyl alcohol (6 mL) at room temperature. This gel column chromatography (EtOAc/hexane, from 1:2 to 2:3) to

solution was maintained at room temperature for 2.5 h and then

concentrated to give the corresponding carboxylic acid as a color-

less oil, which was immediately used in the next reaction without

further purification. Tetramethylsilyldiazomethane (2 m solution in

ether, 140 μL, 280 μmol) was added to a mixture of the crude car-

boxylic acid and benzene/MeOH (4:1, 5 mL) at room temperature.

The reaction was maintained at room temperature for 30 min and

then diluted with H₂O (10 mL). The resulting mixture was ex-

tracted with EtOAc (2ϫ20 mL). The combined organic extracts

were washed with brine (10 mL), dried with Na₂SO₄, and concen-

trated. The residue was purified by silica gel column chromatog-

raphy (EtOAc/hexane, from 1:2 to 2:3) to give methyl ester 49

(57.7 mg, 38% for 3 steps) as a colorless oil. [α]²_D⁶= +2.6 (c = 1.05,

give the pyrrolidine (24.2 mg, 88%) as colorless crystals, m.p. 106–

107 °C. [α]²_D⁶= –8.7 (c = 0.58, CHCl ). IR (film): ν = 2952, 2358,

˜

3

1748, 1674, 1648, 1399, 1209, 839 cm^–1

.

¹H NMR (500 MHz,

C₆D₆): δ = 4.72 (s, 1 H), 4.59 (s, 1 H), 4.49 (d, J = 6.3 Hz, 1 H),

3.89 (d, J = 4.6 Hz, 2 H), 3.38 (s, 3 H), 3.25–3.18 (m, 2 H), 2.59

(s, 3 H), 2.22 (dd, J = 16.3, 4.9 Hz, 1 H), 2.16 (s, 3 H), 2.02 (dd, J

= 16.3, 7.1 Hz, 1 H), 1.47 (s, 3 H) ppm. ¹³C NMR (125 MHz,

C₆D₆): δ = 171.2 (C), 169.5 (C), 159.3 (C), 143.1 (C), 113.7 (CH₂),

93.6 (C), 67.4 (CH), 53.1 (CH₂), 52.2 (CH₃), 47.9 (CH), 41.0 (CH),

36.0 (CH₃), 35.0 (CH₃), 31.8 (CH₂), 22.4 (CH₃) ppm. LRMS (EI):

m/z (%) = 398 (45.3) [M]⁺, 362 (74), 339 (43), 330 (37), 302 (37),

295 (51), 266 (18), 253 (100), 193 (37), 180 (56), 152 (26), 120 (25).

HRMS (EI): calcd. for C₁₅H₂₁Cl₃N₂O₄[M]⁺398.0567; found

398.0566. A solution of the pyrrolidine (12.2 mg, 30.5 μmol), KOH

CHCl ). IR (film): ν = 3237, 2951, 1711, 1640, 1513, 1248,

˜

3

824 cm^–1. H NMR (500 MHz, CDCl₃): δ = 9.11 (d, J = 7.5 Hz, 1 (4 m aqueous solution, 2.0 mL, 8.0 mmol), and tert-butyl alcohol

1

H), 7.23 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 4.89 (dq, (1 mL) was heated to 120 °C and stirred at this temperature for

J = 1.4, 1.4 Hz, 1 H), 4.76–4.75 (m, 1 H), 4.73 (dd, J = 7.5, 2.5 Hz,

1 H), 4.47 (d, J = 12.3 Hz, 1 H), 4.45 (d, J = 12.3 Hz, 1 H), 3.80

6.5 h. After cooling to room temperature, the solution was neutral-

ized by the addition of HCl (4 m aqueous solution, 2.0 mL), and

(s, 3 H), 3.75 (s, 3 H), 3.47 (d, J = 6.3 Hz, 2 H), 2.97 (dddd, J = the resulting mixture was concentrated. A column containing

Eur. J. Org. Chem. 0000, 0–0

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T. Sato, N. Chida et al.

FULL PAPER

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Dowex-50 WX2 hydrogen form (200–400 mesh) was charged with

the residue. After elution (3% aqueous NH₃), the collected frac-

tions were concentrated. The residue was purified by HPLC (Fine-

pak SIL C18S, 150ϫ4.6 mm, UV 200 nm, H₂O, 0.4 mL/min, t_R

=

12.0 min) to afford (–)-kainic acid (41, 4.9 mg, 75%) as colorless

crystals, m.p. 241–243 °C (dec.). [α]²_D⁵= –14.6 (c = 0.43, H₂O);

ref.^[24i][α]²_D³= –14.3 (c = 0.45, H₂O); ref.^[31a][α]²_D⁰= –14.3 (c = 0.40,

H₂O); ref.^[31b][α]_D= –14.6 (c = 0.25, H O). IR (KBr): ν = 3420,

˜

[7]

[8]

2

3100, 2980, 1630, 1580, 1390 cm^–1. ¹H NMR (500 MHz, D₂O): δ

= 5.00 (s, 1 H), 4.71 (s, 1 H), 3.99 (d, J = 3.2 Hz, 1 H), 3.58 (dd,

J = 11.7, 7.2 Hz, 1 H), 3.38 (dd, J = 11.7, 10.3 Hz, 1 H), 3.02–2.93

(m, 2 H), 2.23 (dd, J = 15.5, 6.6 Hz, 1 H), 2.12 (dd, J = 15.5,

8.0 Hz, 1 H), 1.76 (s, 3 H) ppm. ¹³C NMR (125 MHz, D₂O): δ =

178.3 (C), 173.5 (C), 140.1 (C), 113.2 (CH₂), 65.8 (CH), 46.4 (CH₂),

45.8 (CH), 41.4 (CH), 34.9 (CH₂), 22.2 (CH₃) ppm. HRMS (FAB):

calcd. for C₁₀H₁₆NO₄[M + H]⁺214.1079; found 214.1085.

[9]

Supporting Information (see footnote on the first page of this arti-

cle): Procedures and data for all of the new compounds mentioned

in this paper, ¹H and ¹³C NMR, IR, HRMS, and [α]_Dof com-

pounds 12, 13a–13f, 14a–14f, 21a–21c, 21f, 30a–30c, and 30f.

Acknowledgments

[10]

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Support from a Grant-in-Aid for Scientific Research from the Min-

istry of Education, Culture, Sports, Science and Technology, Japan,

grant number B20350021 is gratefully acknowledged. We thank

Prof. Takeshi Noda and Mr. Takuya Shimogaki, of the Kanagawa

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Received: April 21, 2012

Published Online: ᭿

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T. Sato, N. Chida et al.

FULL PAPER

Sigmatropic Rearrangement

K. Kitamoto, Y. Nakayama, M. Sampei,

M. Ichiki, N. Furuya, T. Sato,*

N. Chida* ........................................ 1–16

Chirality Transfers through Sequential Sig-

matropic Rearrangements of Allylic Vicinal

Diols: Development and Application to

Total Synthesis of (–)-Kainic Acid

A detailed investigation is described of two

sequential sigmatropic rearrangements

from allylic diols. Starting from the same

allylic diol, either two identical functional

groups (Claisen/Claisen) or two different

functional groups (Claisen/Overman) were

diastereoselectively installed. The reaction

was successfully applied to the total syn-

thesis of (–)-kainic acid.

Keywords: Rearrangement / Sigmatropic re-

arrangement / Total synthesis / Chirality

transfer / Allylic compounds / Diastereo-

selectivity

16

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Eur. J. Org. Chem. 0000, 0–0

Article Doi

Chirality transfers through sequential sigmatropic rearrangements of allylic vicinal diols: Development and application to total synthesis of (-)-kainic acid

DOI: 10.1002/ejoc.201200523

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201200523

Full text of DOI:10.1002/ejoc.201200523

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